Allosteric Site: A site on an enzyme which upon binding of a modulator, causes the enzyme to undergo a conformational change that may alter its catalytic or binding properties.Allosteric Regulation: The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES.Phthalimides: The imide of phthalic acids.N-Methylscopolamine: A muscarinic antagonist used to study binding characteristics of muscarinic cholinergic receptors.Obidoxime Chloride: Cholinesterase reactivator occurring in two interchangeable isomeric forms, syn and anti.Gallamine Triethiodide: A synthetic nondepolarizing blocking drug. The actions of gallamine triethiodide are similar to those of TUBOCURARINE, but this agent blocks the cardiac vagus and may cause sinus tachycardia and, occasionally, hypertension and increased cardiac output. It should be used cautiously in patients at risk from increased heart rate but may be preferred for patients with bradycardia. (From AMA Drug Evaluations Annual, 1992, p198)Receptor, Muscarinic M2: A specific subtype of muscarinic receptor found in the lower BRAIN, the HEART and in SMOOTH MUSCLE-containing organs. Although present in smooth muscle the M2 muscarinic receptor appears not to be involved in contractile responses.Phosphofructokinases: Allosteric enzymes that regulate glycolysis and gluconeogenesis. These enzymes catalyze phosphorylation of fructose-6-phosphate to either fructose-1,6-bisphosphate (PHOSPHOFRUCTOKINASE-1 reaction), or to fructose-2,6-bisphosphate (PHOSPHOFRUCTOKINASE-2 reaction).Isoindoles: Benzopyrroles with the nitrogen at the number two carbon, in contrast to INDOLES which have the nitrogen adjacent to the six-membered ring.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Receptor, Muscarinic M1: A specific subtype of muscarinic receptor that has a high affinity for the drug PIRENZEPINE. It is found in the peripheral GANGLIA where it signals a variety of physiological functions such as GASTRIC ACID secretion and BRONCHOCONSTRICTION. This subtype of muscarinic receptor is also found in neuronal tissues including the CEREBRAL CORTEX and HIPPOCAMPUS where it mediates the process of MEMORY and LEARNING.Tacrine: A cholinesterase inhibitor that crosses the blood-brain barrier. Tacrine has been used to counter the effects of muscle relaxants, as a respiratory stimulant, and in the treatment of Alzheimer's disease and other central nervous system disorders.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Kinetics: The rate dynamics in chemical or physical systems.Ligands: A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)Radioligand Assay: Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders).Glycogen Phosphorylase, Muscle Form: An isoenzyme of GLYCOGEN PHOSPHORYLASE that catalyzes the degradation of GLYCOGEN in muscle. Mutation of the gene coding this enzyme is the cause of McArdle disease (GLYCOGEN STORAGE DISEASE TYPE V).Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.Adenosine Monophosphate: Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position.Fructose-Bisphosphatase: An enzyme that catalyzes the conversion of D-fructose 1,6-bisphosphate and water to D-fructose 6-phosphate and orthophosphate. EC 3.1.3.11.Fructosediphosphates: Diphosphoric acid esters of fructose. The fructose-1,6- diphosphate isomer is most prevalent. It is an important intermediate in the glycolysis process.Crystallography, X-Ray: The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Protein Structure, Quaternary: The characteristic 3-dimensional shape and arrangement of multimeric proteins (aggregates of more than one polypeptide chain).CHO Cells: CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.Protein Structure, Tertiary: The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.Binding, Competitive: The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.Ribonucleotide ReductasesMutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.Cyclic Nucleotide Phosphodiesterases, Type 5: A cyclic nucleotide phosphodiesterase subfamily that is highly specific for CYCLIC GMP. It is found predominantly in vascular tissue and plays an important role in regulating VASCULAR SMOOTH MUSCLE contraction.HexosediphosphatesAmino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Small Molecule Libraries: Large collections of small molecules (molecular weight about 600 or less), of similar or diverse nature which are used for high-throughput screening analysis of the gene function, protein interaction, cellular processing, biochemical pathways, or other chemical interactions.Receptors, Muscarinic: One of the two major classes of cholinergic receptors. Muscarinic receptors were originally defined by their preference for MUSCARINE over NICOTINE. There are several subtypes (usually M1, M2, M3....) that are characterized by their cellular actions, pharmacology, and molecular biology.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Cytidine Diphosphate: Cytidine 5'-(trihydrogen diphosphate). A cytosine nucleotide containing two phosphate groups esterified to the sugar moiety. Synonyms: CRPP; cytidine pyrophosphate.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Receptor, Muscarinic M4: A specific subtype of muscarinic receptor found in the CORPUS STRIATUM and the LUNG. It has similar receptor binding specificities to MUSCARINIC RECEPTOR M1 and MUSCARINIC RECEPTOR M2.Adenosine Triphosphate: An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.Drug Discovery: The process of finding chemicals for potential therapeutic use.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Cricetulus: A genus of the family Muridae consisting of eleven species. C. migratorius, the grey or Armenian hamster, and C. griseus, the Chinese hamster, are the two species used in biomedical research.Muscarinic Agonists: Drugs that bind to and activate muscarinic cholinergic receptors (RECEPTORS, MUSCARINIC). Muscarinic agonists are most commonly used when it is desirable to increase smooth muscle tone, especially in the GI tract, urinary bladder and the eye. They may also be used to reduce heart rate.Glucose-6-Phosphate: An ester of glucose with phosphoric acid, made in the course of glucose metabolism by mammalian and other cells. It is a normal constituent of resting muscle and probably is in constant equilibrium with fructose-6-phosphate. (Stedman, 26th ed)Receptors, Metabotropic Glutamate: Cell surface proteins that bind glutamate and act through G-proteins to influence second messenger systems. Several types of metabotropic glutamate receptors have been cloned. They differ in pharmacology, distribution, and mechanisms of action.Affinity Labels: Analogs of those substrates or compounds which bind naturally at the active sites of proteins, enzymes, antibodies, steroids, or physiological receptors. These analogs form a stable covalent bond at the binding site, thereby acting as inhibitors of the proteins or steroids.3',5'-Cyclic-GMP Phosphodiesterases: Enzymes that catalyze the hydrolysis of cyclic GMP to yield guanosine-5'-phosphate.Carbolines: A group of pyrido-indole compounds. Included are any points of fusion of pyridine with the five-membered ring of indole and any derivatives of these compounds. These are similar to CARBAZOLES which are benzo-indoles.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Adenosine Diphosphate: Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position.Escherichia coli: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.Protein Structure, Secondary: The level of protein structure in which regular hydrogen-bond interactions within contiguous stretches of polypeptide chain give rise to alpha helices, beta strands (which align to form beta sheets) or other types of coils. This is the first folding level of protein conformation.Nicotinic Acids: 2-, 3-, or 4-Pyridinecarboxylic acids. Pyridine derivatives substituted with a carboxy group at the 2-, 3-, or 4-position. The 3-carboxy derivative (NIACIN) is active as a vitamin.Models, Chemical: Theoretical representations that simulate the behavior or activity of chemical processes or phenomena; includes the use of mathematical equations, computers, and other electronic equipment.Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.Enzyme Activation: Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.Nucleotides: The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed)Drug Design: The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis.Molecular Dynamics Simulation: A computer simulation developed to study the motion of molecules over a period of time.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.Hydrogen Bonding: A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds.Uridine Triphosphate: Uridine 5'-(tetrahydrogen triphosphate). A uracil nucleotide containing three phosphate groups esterified to the sugar moiety.Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Piperidines: A family of hexahydropyridines.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Magnesium: A metallic element that has the atomic symbol Mg, atomic number 12, and atomic weight 24.31. It is important for the activity of many enzymes, especially those involved in OXIDATIVE PHOSPHORYLATION.Catalysis: The facilitation of a chemical reaction by material (catalyst) that is not consumed by the reaction.Receptors, G-Protein-Coupled: The largest family of cell surface receptors involved in SIGNAL TRANSDUCTION. They share a common structure and signal through HETEROTRIMERIC G-PROTEINS.Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Hydrogen-Ion Concentration: The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH = log 1/2[1/(H+)], where (H+) is the hydrogen ion concentration in gram equivalents per liter of solution. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Amides: Organic compounds containing the -CO-NH2 radical. Amides are derived from acids by replacement of -OH by -NH2 or from ammonia by the replacement of H by an acyl group. (From Grant & Hackh's Chemical Dictionary, 5th ed)Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Cyclic GMP: Guanosine cyclic 3',5'-(hydrogen phosphate). A guanine nucleotide containing one phosphate group which is esterified to the sugar moiety in both the 3'- and 5'-positions. It is a cellular regulatory agent and has been described as a second messenger. Its levels increase in response to a variety of hormones, including acetylcholine, insulin, and oxytocin and it has been found to activate specific protein kinases. (From Merck Index, 11th ed)Sequence Homology, Amino Acid: The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.Aspartate Carbamoyltransferase: An enzyme that catalyzes the conversion of carbamoyl phosphate and L-aspartate to yield orthophosphate and N-carbamoyl-L-aspartate. (From Enzyme Nomenclature, 1992) EC 2.1.3.2.Disulfides: Chemical groups containing the covalent disulfide bonds -S-S-. The sulfur atoms can be bound to inorganic or organic moieties.Zinc: A metallic element of atomic number 30 and atomic weight 65.38. It is a necessary trace element in the diet, forming an essential part of many enzymes, and playing an important role in protein synthesis and in cell division. Zinc deficiency is associated with ANEMIA, short stature, HYPOGONADISM, impaired WOUND HEALING, and geophagia. It is known by the symbol Zn.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Enzyme-mononucleotide interactions: three different folds share common structural elements for ATP recognition. (1/1100)

Three ATP-dependent enzymes with different folds, cAMP-dependent protein kinase, D-Ala:D-Ala ligase and the alpha-subunit of the alpha2beta2 ribonucleotide reductase, have a similar organization of their ATP-binding sites. The most meaningful similarity was found over 23 structurally equivalent residues in each protein and includes three strands each from their beta-sheets, in addition to a connecting loop. The equivalent secondary structure elements in each of these enzymes donate four amino acids forming key hydrogen bonds responsible for the common orientation of the "AMP" moieties of their ATP-ligands. One lysine residue conserved throughout the three families binds the alpha-phosphate in each protein. The common fragments of structure also position some, but not all, of the equivalent residues involved in hydrophobic contacts with the adenine ring. These examples of convergent evolution reinforce the view that different proteins can fold in different ways to produce similar structures locally, and nature can take advantage of these features when structure and function demand it, as shown here for the common mode of ATP-binding by three unrelated proteins.  (+info)

A 20-kDa domain is required for phosphatidic acid-induced allosteric activation of phospholipase D from Streptomyces chromofuscus. (2/1100)

Two phospholipase D (PLD) enzymes with both hydrolase and transferase activities were isolated from Streptomyces chromofuscus. There were substantial differences in the kinetic properties of the two PLD enzymes towards monomeric, micellar, and vesicle substrates. The most striking difference was that the higher molecular weight enzyme (PLD57 approximately 57 kDa) could be activated allosterically with a low mole fraction of phosphatidic acid (PA) incorporated into a PC bilayer (Geng et al., J. Biol. Chem. 273 (1998) 12195-12202). PLD42/20, a tightly associated complex of two peptides, one of 42 kDa and the other 20 kDa, had a 4-6-fold higher Vmax toward PC substrates than PLD57 and was not activated by PA. N-Terminal sequencing of both enzymes indicated that both components of PLD42/20 were cleavage products of PLD57. The larger component included the N-terminal segment of PLD57 and contained the active site. The N-terminus of the smaller peptide corresponded to the C-terminal region of PLD57; this peptide had no PLD activity by itself. Increasing the pH of PLD42/20 to 8.9, followed by chromatography of PLD42/20 on a HiTrap Q column at pH 8.5 separated the 42- and 20-kDa proteins. The 42-kDa complex had about the same specific activity with or without the 20-kDa fragment. The lack of PA activation for the 42-kDa protein and for PLD42/20 indicates that an intact C-terminal region of PLD57 is necessary for activation by PA. Furthermore, the mechanism for transmission of the allosteric signal requires an intact PLD57.  (+info)

Stimulation of P-glycoprotein-mediated drug transport by prazosin and progesterone. Evidence for a third drug-binding site. (3/1100)

P-glycoprotein is a plasma membrane protein of mammalian cells that confers multidrug resistance by acting as a broad-specificity, ATP-dependent efflux transporter of diverse lipophilic neutral or cationic compounds. Previously, we identified two positively cooperative drug-binding sites of P-glycoprotein involved in transport [Shapiro, A. B. & Ling, V. (1997) Eur. J. Biochem. 250, 130-137]. The H site is selective for Hoechst 33342 and colchicine. The R site is selective for rhodamine 123 and anthracyclines. Substrate binding to one site stimulates transport by the other. In this paper, we show that prazosin and progesterone stimulate the transport of both Hoechst 33342 and rhodamine 123. Rhodamine 123 and prazosin (or progesterone) in combination stimulate Hoechst 33342 transport in an additive manner. In contrast, Hoechst 33342 and either prazosin or progesterone interfere with each other, so that the stimulatory effect of the combination on rhodamine 123 transport is less than that of each individually. Non-P-glycoprotein-specific effects of prazosin on membrane fluidity and permeability were excluded. These results indicate the existence of a third drug-binding site on P-glycoprotein with a positive allosteric effect on drug transport by the H and R sites. This allosteric site appears to be one of the sites of photoaffinity labeling of P-glycoprotein by [125I]iodoarylazidoprazosin [Safa, A. R., Agresti, M., Bryk, D. & Tamai, I. (1994) Biochemistry 33, 256-265] and is likely not to be capable of drug transport.  (+info)

Flavodoxin: an allosteric inhibitor of AMP nucleosidase from Azotobacter vinelandii. (4/1100)

Flavodoxin, which participates in nitrogen fixation, was found to be a potent allosteric inhibitor of AMP nucleosidase [EC 3.2.2.4] from Azotobacter vinelandii. It inhibited the enzyme by decreasing its affinity for ATP without affecting the maximum velocity. The inhibition constant for flavodoxin was estimated to be 10 muM, which is within the range of physiological concentration in the cells. The concentration of flavodoxin able to alter the activity in vitro suggests that this phenomenon could be of significance in the regulation of flavin biosynthesis in vivo. Flavin mononucleotide (FMN), a prosthetic group of flavodoxin, was also found to act as an allosteric inhibitor. Since no inhibitory action of apo-flavodoxin was observed, it was concluded that the FMN chromophore of the flavodoxin is responsible for the inhibition of the enzyme by this protein.  (+info)

Structural elements of the gamma-aminobutyric acid type A receptor conferring subtype selectivity for benzodiazepine site ligands. (5/1100)

gamma-aminobutyric acid type A (GABAA) receptors comprise a subfamily of ligand-gated ion channels whose activity can be modulated by ligands acting at the benzodiazepine binding site on the receptor. The benzodiazepine binding site was characterized using a site-directed mutagenesis strategy in which amino acids of the alpha5 subunit were substituted by their corresponding alpha1 residues. Given the high affinity and selectivity of alpha1-containing compared with alpha5-containing GABAA receptors for zolpidem, mutated alpha5 subunits were co-expressed with beta2 and gamma2 subunits, and the affinity of recombinant receptors for zolpidem was measured. One alpha5 mutant (bearing P162T, E200G, and T204S) exhibited properties similar to that of the alpha1 subunit, notably high affinity zolpidem binding and potentiation by zolpidem of GABA-induced chloride current. Two of these mutations, alpha5P162T and alpha5E200G, might alter binding pocket conformation, whereas alpha5T204S probably permits formation of a hydrogen bond with a proton acceptor in zolpidem. These three amino acid substitutions also influenced receptor affinity for CL218872. Our data thus suggest that corresponding amino acids of the alpha1 subunit, particularly alpha1-Ser204, are the crucial residues influencing ligand selectivity at the binding pocket of alpha1-containing receptors, and a model of this binding pocket is presented.  (+info)

Metal complexes as allosteric effectors of human hemoglobin: an NMR study of the interaction of the gadolinium(III) bis(m-boroxyphenylamide)diethylenetriaminepentaacetic acid complex with human oxygenated and deoxygenated hemoglobin. (6/1100)

The boronic functionalities on the outer surface of the Gd(III) bis(m-boroxyphenylamide)DTPA complex (Gd(III)L) enable it to bind to fructosamine residues of oxygenated glycated human adult hemoglobin. The formation of the macromolecular adduct can be assessed by NMR spectroscopy via observation of the enhancement of the solvent water proton relaxation rate. Unexpectedly, a strong binding interaction was also observed for the oxygenated unglycated human adult hemoglobin, eventually displaying a much higher relaxation enhancement. From relaxation rate measurements it was found that two Gd(III)L complexes interact with one hemoglobin tetramer (KD = 1.0 x 10(-5) M and 4.6 x 10(-4) M, respectively), whereas no interaction has been observed with monomeric hemoproteins. A markedly higher affinity of the Gd(III)L complex has been observed for oxygenated and aquo-met human adult hemoglobin derivatives with respect to the corresponding deoxy derivative. Upon binding, a net change in the quaternary structure of hemoglobin has been assessed by monitoring the changes in the high-resolution 1H-NMR spectrum of the protein as well as in the Soret absorption band. On the basis of these observations and the 11B NMR results obtained with the diamagnetic La(III)L complex, we suggest that the interaction between the lanthanide complex and deoxygenated, oxygenated, and aquo-met derivatives of human adult hemoglobin takes place at the 2, 3-diphosphoglycerate (DPG) binding site, through the formation of N-->B coordinative bonds at His143beta and His2beta residues of different beta-chains. The stronger binding to the oxygenated form is then responsible for a shift of the allosteric equilibrium toward the high-affinity R-state. Accordingly, Gd(III)L affinity for oxygenated human fetal hemoglobin (lacking His143beta) is significantly lower than that observed for the unglycated human adult tetramer.  (+info)

Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. (7/1100)

Sialuria is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free N-acetylneuraminic acid (NeuAc, sialic acid). Overproduction of NeuAc is believed to result from loss of feedback inhibition of uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac). We report the cloning and characterization of human UDP-GlcNAc 2-epimerase cDNA, with mutation analysis of three patients with sialuria. Their heterozygote mutations, R266W, R266Q, and R263L, indicate that the allosteric site of the epimerase resides in the region of codons 263-266. The heterozygous nature of the mutant allele in all three patients reveals a dominant mechanism of inheritance for sialuria.  (+info)

Steric effects on multivalent ligand-receptor binding: exclusion of ligand sites by bound cell surface receptors. (8/1100)

Steric effects can influence the binding of a cell surface receptor to a multivalent ligand. To account for steric effects arising from the size of a receptor and from the spacing of binding sites on a ligand, we extend a standard mathematical model for ligand-receptor interactions by introducing a steric hindrance factor. This factor gives the fraction of unbound ligand sites that are accessible to receptors, and thus available for binding, as a function of ligand site occupancy. We derive expressions for the steric hindrance factor for various cases in which the receptor covers a compact region on the ligand surface and the ligand expresses sites that are distributed regularly or randomly in one or two dimensions. These expressions are relevant for ligands such as linear polymers, proteins, and viruses. We also present numerical algorithms that can be used to calculate steric hindrance factors for other cases. These theoretical results allow us to quantify the effects of steric hindrance on ligand-receptor kinetics and equilibria.  (+info)

*Phosphofructokinase 2

The allosteric regulation of PFK2 is very similar to the regulation of PFK1. High levels of AMP or phosphate group signifies a ... Properties of phospho- and dephospho- forms and of two mutants in which Ser32 has been changed by site-directed mutagenesis". J ... Kurland I, Chapman B, Lee YH, Pilkis S (August 1995). "Evolutionary reengineering of the phosphofructokinase active site: ARG- ... plus an additional α-helical subdomain that covers the presumed active site of the molecule. Finally, N-terminal region ...

*NMDA receptor antagonist

... which bind to and block the glycine site; noncompetitive antagonists, which inhibit NMDARs by binding to allosteric sites; and ... Lipina, T; Labrie V, Weiner I, Roder J (2005). "Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, ... Aptiganel (Cerestat, CNS-1102): binds the Mg2+ binding site within the channel of the NMDA receptor. HU-211: an enantiomer of ... These drugs act at the glycine binding site: Rapastinel (GLYX-13) (weak partial agonist; IA = ~20%) NRX-1074 (weak partial ...

*Resistance mutation

Without access to the allosteric site, the NNRTI will not be effective. Integrase inhibitors prevent the HIV integrase enzyme ... Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site on it. ... Protease inhibitors bind to the active site of the viral protease, which prevents the cleavage of the Gag and Gagpol proteins. ...

*Ribose-phosphate diphosphokinase

The allosteric site, which binds ADP, consists of amino acid residues from three subunits. The product of this reaction, ... At normal concentrations, phosphate activates the enzyme by binding to its allosteric regulatory site. However, at high ... "Crystal structure of human phosphoribosylpyrophosphate synthetase 1 reveals a novel allosteric site". Biochem. J. 401 (1): 39- ... The catalytic site of the enzyme binds ATP and ribose 5-phosphate. The flexible loop (Phe92-Ser108), pyrophosphate binding loop ...

*Mixed inhibition

In mixed inhibition, the inhibitor binds to an allosteric site, i.e. a site different from the active site where the substrate ... However, not all inhibitors that bind at allosteric sites are mixed inhibitors. Mixed inhibition may result in either: A ...

*Reagent

... drug discovery targeting allosteric sites". Journal of Medicinal Chemistry. 57 (18): 7485-7498. doi:10.1021/jm5011786. PMC ...

*Ribonucleotide reductase

When ATP binds to the allosteric activity site, it activates RNR. In contrast, when dATP binds to this site, it deactivates RNR ... RNR1 contains both allosteric sites, mediating regulation of substrate specificity and activity. Depending on the allosteric ... In all classes, binding of ATP or dATP to the allosteric site induces reduction of cytidine 5'-diphosphate (CDP) and uridine 5 ... in the active site. Site-directed mutations of the RNR primary structure indicate that all residues cited above participate in ...

*Malate dehydrogenase 2

Evidence for an allosteric citrate-binding site". The Journal of Biological Chemistry. 257 (22): 13233-9. PMID 7142142. Gelpí ... Evidence for an allosteric citrate-binding site". The Journal of Biological Chemistry. 257 (22): 13233-9. PMID 7142142. Harada ... All three effectors (malate, oxaloacetate and citrate) bind to the same putative allosteric site. Recent studies of ... The active sites in these dimeric proteins are well separated from each other. Because malate dehydrogenase is closely tied to ...

*Enzyme kinetics

In noncompetitive inhibition, the inhibitor will bind to an enzyme at its allosteric site; therefore, the binding affinity, or ... with binding of substrate to one active site altering the affinity of the other active sites for substrate molecules. Positive ... Alternatively, the observation of a strong pH effect on Vmax but not Km might indicate that a residue in the active site needs ... In these serine proteases, the E* intermediate is an acyl-enzyme species formed by the attack of an active site serine residue ...

*GAT100

"Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)". Journal of ... "Mapping Cannabinoid 1 Receptor Allosteric Site(s): Critical Molecular Determinant and Signaling Profile of GAT100, a Novel, ... GAT100 is a negative allosteric modulator of the cannabinoid CB1 receptor. Org 27569 PSNCBAM-1 ZCZ-011 Pushkar M. Kulkarni; ...

*Reuptake inhibitor

Notably, this allosteric site may be directly related to the above-mentioned PCP binding sites. A second type of reuptake ... Instead of binding to the active site on the serotonin transporter, they bind to an allosteric site, which exerts its effects ... They appear to exert their reuptake inhibition by binding to vaguely characterized allosteric sites on each of the respective ... Alternatively, some reuptake inhibitors bind to allosteric sites and inhibit reuptake indirectly and noncompetitively. ...

*Metabotropic glutamate receptor 1

In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinct allosteric ... "A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from ... a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric ... "Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists ...

*Receptor antagonist

Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact ... This may be accomplished by binding to the active site or the allosteric site. In addition, antagonists may interact at unique ... by binding to the active site of the receptor or by binding to an allosteric site of the receptor; in the latter case, the ... act at an allosteric site. These antagonists bind to a distinctly separate binding site from the agonist, exerting their action ...

*Cyclothiazide

"Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists ... In 1993, it was discovered that cyclothiazide is a positive allosteric modulator of the AMPA and kainate receptors, capable of ... AMPA receptor positive allosteric modulator Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug ... ISBN 0-8155-1144-2. Skolnick, Phil; Palfreyman, Michael G.; Reynolds, Ian J. (1994). Direct and allosteric control of glutamate ...

*PYGL

... and the AMP site, which is connected to the active site by an adenine loop. Phosphorylation or binding of the allosteric sites ... The catalytic site forms at the interface between these two domains and interacts with the required cofactor, pyridoxal ... PYGL has been known to interact with allosteric inhibitors, including Bayer W1807 and sugar derivatives that bind the glucose ... In addition, glucose and purines stabilize the inactive conformation of PYGL, thus inhibiting binding to its active site. ...

*Sucrose-phosphate synthase

Glucose 6-phosphate binds to an allosteric site, resulting in conformational changes to SPS that increase the enzyme's affinity ... Inorganic phosphate can also bind to this allosteric site, preventing glucose 6-phosphate activation of SPS. Like regulation ... SPS-kinase reversibly phosphorylates a serine residue and subsequently deactivates SPS, In spinach and maize, the site of ... and is an excellent example of various key enzyme regulation strategies such as allosteric control and reversible ...

*1-phosphofructokinase

There are two ATP binding sites; a substrate site where the phosphate transfer occurs, and an allosteric site where allosteric ... In addition to the catalytic binding sites, there are 4 additional binding sites for allosteric regulation. 1- ... ATP acts as an allosteric inhibitor and when cellular concentrations of ATP are high, and the cell's energy needs are low, the ... Allosteric regulation of 1-phosphofructokinase is facilitated hormonally to help the liver to maintain blood glucose levels. ...

*Epimerox

For enzymatic activity, the allosteric site needs to be occupied by the substrate UDP-N-acetylglucosamine; this is the first ... Because epimerox targets the allosteric site of the bacterial 2-epimerase, low human toxicity is expected since the human 2- ... Bacterial 2-epimerase differs from its human counterpart in that the bacterial molecule has an allosteric site. ... enzyme described in which the substrate is present in both the catalytic and allosteric sites. ...

*Discovery and development of phosphodiesterase 5 inhibitors

The R domain contains specific allosteric cGMP binding site that controls the enzymes function. This specific binding site ... The allosteric binding site GAF consists of GAFa and GAFb where GAFa has a higher binding affinity. The importance and ... Turko, I. V.; Francis, S. H.; Corbin, J. D. (1998). "Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific ... Phosphorylation of a single serine by PKG1 and the allosteric cGMP binding site activates the PDE5 catalytic activity and the ...

*Cochlear amplifier

Under resting conditions, it is thought that chloride is bound to allosteric sites in prestin. Upon deflection of the BM ... Intracellular chloride dissociates from the allosteric binding sites in prestin, causing contraction of prestin. Upon BM ... Additionally, Ca2+ briefly binds to a cytostolic site on the MET channel which is estimated to be only 5 nm from the channel ... Due to the differences in calcium concentration at the cytostolic binding site when calcium is bound to the MET channel versus ...

*Galantamine

... galantamine binds to the allosteric sites of nicotinic receptors, which causes a conformational change. This allosteric ... By binding to the allosteric site of the nAChRs, a conformational change occurs which increases the receptors response to ... Galantamine is a potent allosteric potentiating ligand of human nicotinic acetylcholine receptors (nAChRs) α4β2, α3β4, and α6β4 ... CS1 maint: Multiple names: authors list (link) Razadyne ER (manufacturer's website) Proteopedia 1dx6 AChE inhibitors and ...

*KMT2A

... activation domain binds to an allosteric site on the KIX domain". The Journal of Biological Chemistry. 277 (45): 43168-74. doi: ... activation domain binds to an allosteric site on the KIX domain". The Journal of Biological Chemistry. 277 (45): 43168-74. doi: ...

*CREB-binding protein

... activation domain binds to an allosteric site on the KIX domain". The Journal of Biological Chemistry. 277 (45): 43168-74. doi: ... Out of the described phosphoacceptor sites, serines 2361, 2363, 2371, 2376, and 2381 are responsible for the HIPK2-induced ...

*AFDX-384

... possible involvement of the common allosteric site". Molecular Pharmacology. 53 (2): 304-12. PMID 9463489. Kitaichi K, Day JC, ...

*Transactivation domain

... activation domain binds to an allosteric site on the KIX domain". The Journal of Biological Chemistry. 277 (45): 43168-74. doi: ... These binding sites are frequently referred to as activation functions (AFs). TADs are named after their amino acid composition ... is a transcription factor scaffold domain which contains binding sites for other proteins such as transcription coregulators. ... "Use of a genetically introduced cross-linker to identify interaction sites of acidic activators within native transcription ...

*Prostaglandin-endoperoxide synthase 2

... and an allosteric monomer (E-allo). Heme binds only to the peroxidase site of E-cat while substrates, as well as certain ... Each monomer of the enzyme has a peroxidase and a PTGS (COX) active site. The PTGS (COX) enzymes catalyze the conversion of ... Second, PGG2 is reduced to PGH2 in the peroxidase active site. The synthesized PGH2 is converted to prostaglandins (PGD2, PGE2 ... Both the cyclooxygenase and the peroxidase active sites are located in the catalytic domain, which accounts for approximately ...

*Paroxetine

It also binds to the allosteric site of the serotonin transporter, similarly, but less potently, than escitalopram. Paroxetine ...
Multiple allosteric sites on muscarinic receptors.: Proteins and small molecules are capable of regulating the agonist binding and function of G-protein coupled
Possible location the allosteric binding pocket of L. pneumophila dehydratase. The catalytic domain is highlightedin orange, whereasthe β domain is displayed i
View Notes - L0710ap from BIOS 20182 at UChicago. committed step in a pathway Allosteric regulation (mechanism) Binding of ATP to a non-substrate (allosteric) site on the enzyme causes a
The RAS/RAF/MEK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. Several allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor-resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed that both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK-resistant ...
5713 The concept of mitotic inhibition regained special attention after identification of the mitotic kinesin Eg5, which was validated as a drugable target using a chemical genetics approach. Eg5 inhibitors target a core component of dividing cells but may have an improved side effect profile in comparison to drugs interfering with tubulin dynamics. Here, we disclose a novel and promising class of Eg5 inhibitors. A broad lead optimization program of the hexahydropyranoquinoline (HHPQ) class, identified by an HTS campaign, revealed potent and selective inhibitors of the mitotic ATPase Eg5. Those Eg5 inhibitors specifically and reversibly dock into an allosteric binding pocket unique to Eg5, which is proven by X-ray crystallography and Biacore® binding studies. Proliferation in multiple cancer cell lines (e.g., Colo205, HCT116, SW707, MDA-MB468) is potently inhibited due to profound mitotic arrest with subsequent apoptosis. In vivo studies in mouse xenograft models using i.p. as well as oral ...
1NHU: Non-Nucleoside Analogue Inhibitors Bind to an Allosteric Site on HCV NS5B Polymerase: Crystal Structures and Mechanism of Inhibition
27 Jan 2009 Direct updating of content on a live Flash website. • No client They provide pre-scripted and customizable Feedback form. But their Flash Escitalopram, also known by the brand names Lexapro and Cipralex among others, is an For its racemic form, see citalopram. . enhances its own binding via an additional interaction with another allosteric site on the transporter. This pushed the patent expiration date from December 7, 2009 to September 14, 2011. My name is Lexa Ryan and Im so very pleased youve found your way to me. beautifully in tune with human sensuality in its many and varied forms. . with any person whose contact information appears on this Site -request, solicit, .. and after the date you affix your digital signature and continuously access this Site.Main Page · By Date · Top 800 By Year · Top 800 By Decade · Book Guide 3) If you are having a problem with our website, please fill out a problem report. LCs 01 James Isaac directed, Kane Hodder, Lexa Doig, evil gets an ...
On the basis of its MEK inhibitory activity, E6201 was shown here to be an ATP-competitive MEK inhibitor that is effective against BRAF-V600E melanoma in a preclinical setting. Furthermore, we showed that E6201 is effective in a preclinical model against BRAF-V600E melanoma harboring the MEK1-C121S mutation. Almost all of the MEK inhibitors previously reported are allosteric inhibitors, not ATP-competitive inhibitors (37). Our docking simulation showed that E6201 and selumetinib bind to different sites when they dock with MEK. These results suggest that the inhibitory mode of action of E6201 is different from that of allosteric MEK inhibitors and that E6201 merits further investigation in a clinical setting against both MEK-WT melanomas and melanomas harboring MEK with mutations at the allosteric site.. The MEK1-C121S mutation, which confers resistance to vemurafenib, increases MEK activity independently from BRAF and also confers resistance to the allosteric MEK inhibitor selumetinib (12). Our ...
Cpd 1 and 2 bind the inhibitor site, where Cpd 3 binds the new allosteric site. Cpds 4 and 5 are proposed analogs of 2, Cpds 6 and 7 are analogs of 3, and Cpds 8 and 9 are "frequent-hitters". NOESY experiments were recorded for the six fragments in the presence of 2 and 3. All compounds exhibited intramolecular NOEs upon binding to the target. Additionally, Cpds 2 and 4/5 showed intermolecular NOEs, as did Cpd 3 with 6, 7, 8, and 9. Cpds 4 and 5 did not shows NOEs with 3, nor did 6, 7, 8, and 9 show NOEs to Cpd 2. For fragments 4-7, competition data support that these are inter-ligand NOEs and that Cpds 8 and 9 are non-specific binders. No intermolecular NOEs were seen to Cpd 1. Cpd 1 has a IC50 of 1 uM, while Cpd 2 is 100uM. This supports theoretical calculations that the two competitive binders must have binding constants no more than 8x different ...
In the wild-type receptor, the sodium ion alternates direct interactions with Ser913.39 and Asn2807.45 in two distinct resonance positions, as predicted in MD simulations [Table 5; Gutiérrez-de-Terán et al. (2013b)], while maintaining contact with Asp522.50. This is in agreement with the observation that sodium ion modulation of agonist binding is not completely abolished in mutant receptors S91A3.39 and N280A7.45 (Fig. 3A) and that the two remaining residues in mutants S91A3.39 and N280A7.45 (Asp522.50, and Asn2807.45, or Ser913.39, respectively) still interact directly with the sodium ion, although less than in the wild-type receptor (Table 5). Jiang et al. (1996) found that the same S91A mutation did not affect orthosteric ligand binding very much, even less so than the slight decrease in affinity in our experiments (Table 1). In the adenosine A1 receptor, however, orthosteric ligand binding could not be detected for this mutation, maybe due to lack of expression (Barbhaiya et al., ...
Compounds are evaluated for their binding to naturally occurring receptors, by employing the natural ligand conjugated to an enzyme donor fragment of β-galactosidase for competing with the sample compound for the natural acceptor binding site or in the absence of competition where the sample compound binds to an allosteric site. By adding the enzyme acceptor fragment of the β-galactosidase and substrate, the binding affinity of the sample compound may be evaluated as a measure of agonist or antagonist capability.
TY - JOUR. T1 - Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors. AU - Arias, H. R.. AU - Xing, H.. AU - MacDougall, K.. AU - Blanton, M. P.. AU - Soti, F.. AU - Kern, W. R.. PY - 2009/5/1. Y1 - 2009/5/1. N2 - Background and purpose: Benzylidene-anabaseines (BAs) are partial agonists of the α7 nicotinic acetylcholine receptor (nAChR) but their mechanism(s) of action are unknown. Our study explores several possibilities, including direct interactions of BAs with the nAChR channel. Experimental approach: Functional and radioligand-binding assays were used to examine the interaction of two BA analogues, 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) and Its primary metabolite 3-(4-hydroxy-2-methoxybenzylidene)anabaseine (4OH-DMXBA) with both agonist and non-competitive antagonist (NCA)-bindlng sites on muscle-type nAChRs. Key results: Both BAs non-competitively inhibited ACh activation of human fetal muscle nAChRs and ...
BioAssay record AID 581576 submitted by ChEMBL: Displacement of [3H]3-methoxy-PEPy from rat mGluR5 receptor allosteric binding site at 30 uM.
Negative allosteric modulation (also known as allosteric inhibition) occurs when the binding of one ligand decreases the affinity for substrate at other active sites. For example, when 2,3-BPG binds to an allosteric site on hemoglobin, the affinity for oxygen of all subunits decreases. This is when a regulator is absent from the binding site.. Direct thrombin inhibitors provides an excellent example of negative allosteric modulation. Allosteric inhibitors of thrombin have been discovered which could potentially be used as anticoagulants.. Another example is strychnine, a convulsant poison, which acts as an allosteric inhibitor of the glycine receptor. Glycine is a major post-synaptic inhibitory neurotransmitter in mammalian spinal cord and brain stem. Strychnine acts at a separate binding site on the glycine receptor in an allosteric manner; i.e., its binding lowers the affinity of the glycine receptor for glycine. Thus, strychnine inhibits the action of an inhibitory transmitter, leading to ...
The serotonin transporter (SERT) controls synaptic serotonin levels and is the primary target for antidepressants, including selective serotonin reuptake inhibitors (e.g. (S)-citalopram) and tricyclic antidepressants (e.g. clomipramine). In addition to a high affinity binding site, SERT possesses a low affinity allosteric site for antidepressants. Binding to the allosteric site impedes dissociation of antidepressants from the high affinity site, which may enhance antidepressant efficacy. Here we employ an induced fit docking/molecular dynamics protocol to identify the residues that may be involved in the allosteric binding in the extracellular vestibule located above the central substrate binding (S1) site. Indeed, mutagenesis of selected residues in the vestibule reduces the allosteric potency of (S)-citalopram and clomipramine. The identified site is further supported by the inhibitory effects of Zn(2+) binding in an engineered site and the covalent attachment of ...
1) Allosteric regulation is the regulation of the activity of allosteric enzymes. (See also Allosteric binding sites; Allosteric enzymes).. ...
BioAssay record AID 390611 submitted by ChEMBL: Modulation of human adenosine A1 receptor expressed in CHO-K1 cells assessed as allosteric effect on [125I]ABA dissociation.
Author Summary A common means of biological regulation is allostery, in which an effector molecule binds to one site on a protein and induces a conformational change which changes activity at a distant active site. Frequently high resolution structures are determined for one state of an allosteric protein but not the other. To probe the allosteric conformational changes in such cases, we describe a computational method for predicting the structure of one allosteric state of a protein starting with knowledge of another. Our method also provides a detailed map of the free energy landscape traversed in an allosteric transition and reveals the coupling between interacting residue pairs that underlies the transition.
ITK (interleukin-2-inducible T-cell kinase) is a critical component of signal transduction in T-cells and has a well-validated role in their proliferation, cytokine release and chemotaxis. ITK is an attractive target for the treatment of T-cell-mediated inflammatory diseases. In the present study we describe the discovery of kinase inhibitors that preferentially bind to an allosteric pocket of ITK. The novel ITK allosteric site was characterized by NMR, surface plasmon resonance, isothermal titration calorimetry, enzymology and X-ray crystallography. Initial screening hits bound to both the allosteric pocket and the ATP site. Successful lead optimization was achieved by improving the contribution of the allosteric component to the overall inhibition. NMR competition experiments demonstrated that the dual-site binders showed higher affinity for the allosteric site compared with the ATP site. Moreover, an optimized inhibitor displayed non-competitive inhibition with respect to ATP as shown by ...
Allosteric modulation of adenosine A1 receptors (A1ARs) offers a novel therapeutic approach for the treatment of numerous central and peripheral disorders. However, despite decades of research, there is a relative paucity of structural information regarding the A1AR allosteric site and mechanisms governing cooperativity with orthosteric ligands. We combined alanine-scanning mutagenesis of the A1AR second extracellular loop (ECL2) with radioligand binding and functional interaction assays to quantify effects on allosteric ligand affinity, cooperativity and efficacy. Docking and molecular dynamics (MD) simulations were performed using an A1AR homology model based on an agonist-bound A2AAR structure. Substitution of E172ECL2 for alanine reduced the affinity of the allosteric modulators, PD81723 and VCP171, for the unoccupied A1AR. Residues involved in cooperativity with the orthosteric agonist, NECA, were different between PD81723 and VCP171; positive cooperativity between PD81723 and NECA was ...
USE OF SELECTIVE GABA A ALPHA 5 NEGATIVE ALLOSTERIC MODULATORS FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM CONDITIONS - diagram, schematic, and image 17 ...
This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, l-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on ...
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptors activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist-receptor complex, which, in turn, depends on the nature of antagonist-receptor binding. The majority of drug antagonists achieve their potency by competing with endogenous ligands or ...
I found out that glyphosate is an aminophosphonic analogue of glycine. First question: How is it different? Is there a phosphate group added onto it? What does being an aminophosphonic analogue entail?Now, the analogues act as antimetabolites, which interefere, at least in this case, with the production of the plants amino acids. They compete with normal substrates at the active site, denaturing the enzyme, and making it useless for its original purpose. So here lies my second question: Is there a substrate that is non-competitive to do this same thing OR are there even allosteric sites on such enzymes?Many thanks ...
Davis, B.C.; Brown, J.A.; Thorpe, I.F., 2016: Allosteric inhibitors have distinct effects, but also common modes of action, in the HCV polymerase
The Neddylation pathway was recently validated as a cancer target. The SENP8 protease processes the precursor of Nedd8 and is essential for its activation. Base...
There are 6 different types of ligands that bind the CB1 receptor. What is the difference between an inverse agonist and a negative allosteric modulator?
The main focus of Kelvin Gees UC Irvine laboratory is the characterization of novel allosteric modulatory sites on receptors that are potential drug targets for the treatment of neurological and psychiatric disorders.
1LJM: DNA Recognition by the RUNX1 Transcription Factor Is Mediated by an Allosteric Transition in the RUNT Domain and by DNA Bending.
The conversion of molecule S to product P has a Keq = 2.0. Two different, but related enzymes, A and B, can catalyze the reaction. The product P serves as an allosteric inhibitor of enzyme B, but not of enzyme A. A. 10 mM S is placed ...
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Taiho Pharmaceutical is developing TAS 117, a potent and selective oral allosteric non-ATP-competitive AKT inhibitor, for the treatment of solid tumours. Phase
Looking for online definition of allosteric enzymes in the Medical Dictionary? allosteric enzymes explanation free. What is allosteric enzymes? Meaning of allosteric enzymes medical term. What does allosteric enzymes mean?
TY - JOUR. T1 - Expression, purification and characterization of human glutamate dehydrogenase (GDH) allosteric regulatory mutations. AU - Fang, Jie. AU - Hsu, Betty Y L. AU - MacMullen, Courtney M.. AU - Poncz, Mortimer. AU - Smith, Thomas. AU - Stanley, Charles A.. PY - 2002/4/1. Y1 - 2002/4/1. N2 - Glutamate dehydrogenase (GDH) catalyses the reversible oxidative deamination of L-glutamate to 2-oxoglutarate in the mitochondrial matrix. In mammals, this enzyme is highly regulated by allosteric effectors. The major allosteric activator and inhibitor are ADP and GTP, respectively; allosteric activation by leucine may play an important role in amino acid-stimulated insulin secretion. The physiological significance of this regulation has been highlighted by the identification of children with an unusual hyperinsulinism/hyperammonaemia syndrome associated with dominant mutations in GDH that cause a loss in GTP inhibition. In order to determine the effects of these mutations on the function of the ...
In bacteria, the level of cAMP varies depending on the medium used for growth. In particular, cAMP is low when glucose is the carbon source. This occurs through inhibition of the cAMP-producing enzyme, adenylyl cyclase, as a side-effect of glucose transport into the cell. The transcription factor cAMP receptor protein (CRP) also called CAP (catabolite gene activator protein) forms a complex with cAMP and thereby is activated to bind to DNA. CRP-cAMP increases expression of a large number of genes, including some encoding enzymes that can supply energy independent of glucose. cAMP, for example, is involved in the positive regulation of the lac operon. In an environment of a low glucose concentration, cAMP accumulates and binds to the allosteric site on CRP (cAMP receptor protein), a transcription activator protein. The protein assumes its active shape and binds to a specific site upstream of the lac promoter, making it easier for RNA polymerase to bind to the adjacent promoter to start ...
In bacteria, the level of cAMP varies depending on the medium used for growth. In particular, cAMP is low when glucose is the carbon source. This occurs through inhibition of the cAMP-producing enzyme, adenylyl cyclase, as a side-effect of glucose transport into the cell. The transcription factor cAMP receptor protein (CRP) also called CAP (catabolite gene activator protein) forms a complex with cAMP and thereby is activated to bind to DNA. CRP-cAMP increases expression of a large number of genes, including some encoding enzymes that can supply energy independent of glucose. cAMP, for example, is involved in the positive regulation of the lac operon. In an environment of a low glucose concentration, cAMP accumulates and binds to the allosteric site on CRP (cAMP receptor protein), a transcription activator protein. The protein assumes its active shape and binds to a specific site upstream of the lac promoter, making it easier for RNA polymerase to bind to the adjacent promoter to start ...
Valentini G., Chiarelli L., Fortin R., Speranza M.L., Galizzi A., Mattevi A.. Pyruvate kinase (PK) is critical for the regulation of the glycolytic pathway. The regulatory properties of Escherichia coli were investigated by mutating six charged residues involved in interdomain salt bridges (Arg(271), Arg(292), Asp(297), and Lys(413)) and in the binding of the allosteric activator (Lys(382) and Arg(431)). Arg(271) and Lys(413) are located at the interface between A and C domains within one subunit. The R271L and K413Q mutant enzymes exhibit altered kinetic properties. In K413Q, there is partial enzyme activation, whereas R271L is characterized by a bias toward the T-state in the allosteric equilibrium. In the T-state, Arg(292) and Asp(297) form an intersubunit salt bridge. The mutants R292D and D297R are totally inactive. The crystal structure of R292D reveals that the mutant enzyme retains the T-state quaternary structure. However, the mutation induces a reorganization of the interface with the ...
The GLP-1R is a major target for the treatment and management of type II diabetes but peptides, despite the approval of several drugs (exenatide and liraglutide), do not provide ideal therapeutics because their use is complicated by the route of administration. This has driven the search for low molecular weight, orally active compounds that activate or augment GLP-1R signaling as the idealized therapeutic drug. Recent drug discovery efforts for the GLP-1R have focused on targeting sites for allosteric modulation. Allosteric interactions are often complex because ligands can alter the biological properties of the endogenous ligand by modulating the affinity and/or efficacy as well as having the potential to exhibit their own agonism. This can be complicated if there are multiple endogenous ligands (as is the case for the GLP-1R), because the allosteric interaction can vary with the nature of the orthosteric ligand, a property termed "probe dependence" (May et al., 2007b). These allosteric ...
One problem with undruggable targets is finding the first small-molecule starting point. Fragment-based lead discovery breaks the problem into smaller pieces by testing compounds that are roughly half the size of a typical drug lead. Small compounds with low complexity bind to subsites within a drug-binding site, allowing the researcher to get a foothold. The disulfide trapping method known as Tethering is a site-directed method in which a native or engineered cysteine residue on the protein captures thiol-containing fragments. Tethering-originally developed by James Wells and colleagues at Sunesis Pharmaceuticals-has been further advanced at UCSF after Wells joined the Department of Pharmaceutical Chemistry faculty. UCSF investigators have discovered new allosteric sites with Tethering, and tethered compounds have acted as molecular chaperones for crystallography.. ...
A combined systematic alanine scanning and molecular modelling approach reveals the molecular basis for an allosteric inhibition mechanism of K+-flux gating in K2P channels.
View and buy high purity VU 0424465 from Tocris Bioscience. Potent mGlu5 positive allosteric modulator and agonist; binds allosteric site with high affinity.
The SAMPL4 challenges were used to test current automated methods for solvation energy, virtual screening, pose and affinity prediction of the molecular docking pipeline DOCK 3.7. Additionally, first-order models of binding affinity were proposed as milestones for any method predicting binding affinity. Several important discoveries about the molecular docking software were made during the challenge: (1) Solvation energies of ligands were five-fold worse than any other method used in SAMPL4, including methods that were similarly fast, (2) HIV Integrase is a challenging target, but automated docking on the correct allosteric site performed well in terms of virtual screening and pose prediction (compared to other methods) but affinity prediction, as expected, was very poor, (3) Molecular docking grid sizes can be very important, serious errors were discovered with default settings that have been adjusted for all future work. Overall, lessons from SAMPL4 suggest many changes to molecular docking ...
Sigma-Aldrich offers abstracts and full-text articles by [Erwann Le Rouzic, Damien Bonnard, Sophie Chasset, Jean-Michel Bruneau, Francis Chevreuil, Frédéric Le Strat, Juliette Nguyen, Roxane Beauvoir, Céline Amadori, Julie Brias, Sophie Vomscheid, Sylvia Eiler, Nicolas Lévy, Olivier Delelis, Eric Deprez, Ali Saïb, Alessia Zamborlini, Stéphane Emiliani, Marc Ruff, Benoit Ledoussal, François Moreau, Richard Benarous].
Hello Bio announced today the launch of JF-NP-26 (Caged-Raseglurant) - the first photoactive mGlu5 negative allosteric modulator (NAM) that allows optical control of analgesia in vivo.
The modulation of 5-HT2C receptor (5-HT2CR) function holds a tremendous amount of therapeutic promise for the treatment of diseases of significant unmet medical...
Researchers from the University of Granada have discovered, for the first time, an allosteric interaction (that is, a regulation mechanism whereby enzymes can be activated or de-activated) between this protein, which forms ...
Get an answer for 1. The production of ATP is central to the survival of organisms. This production must be closely regulated to ensure that the needs of the organisms are being met. Considering the structure and function of enzymes and allosteric inhibitors, explain how the production of ATP is able to regulate itself. 2. Discuss the role of NAD+ and NADH in metabolism. Include in your discussion whether on not taking an NADH supplements would be helpful for physical activity. 3.Mr. Friedrichs lungs bra
The conversion of molecule S to product P has a Keq = 2.0. Two different, but related enzymes, A and B, can catalyze the reaction. The product P serves as an allosteric inhibitor of enzyme B, but not of enzyme A. A. 10 mM S is placed ...
Hi, Can anyone please explain what is proteolysis. I looked it up and all I understand is that it is the hydrolysis of proteins which causes them to break down. Is this correct or not? If it is not please tell me what it is? Also please explain what is the Ka-Mg2+ . My understanding is that ka is the acid dissociation constant. But I thought that applied to acid which gain electron. But how does it apply to Mg2+. If I am totally wrong please explain what it may be. I am reading an article on Allosteric inhibition of Fructose-1,6-bisphosphate and it says that mutated ones have a higher Ka-Mg2+. what does that mean? Thanx ...
One of the basic properties of protein|proteins is the ability to bind things ... things such as DNA, drugs, other proteins, cell surfaces, etc ... The ...
Buy YM-01 (YM-1) (CAS 409086-68-6), a water soluble allosteric Hsp70 modulator; potent anti-tau agent. Join researchers using high quality YM-01 (YM-1) from…
Abstract: : Purpose:Transducin activation by rhodopsin has been shown under positive allosteric control (Wessling-Resnick and Johnson, JBC 262,3996 (1987)). The origin of this allosteric behavior has not been identified. Chemical cross-linking study (Hingorani, et al., JBC,259,6694 (1984)) suggested that transducin forms supermolecular structure as large as [Tαßγ]4 in solution. In this study, the role of the tetrameric [Tαßγ]4 on the allosteric behavior of transducin is investigated. Methods:Correlations of the tetrameric transducin [Tαßγ]4 and its binding to rhodopsin have been studied by analytical ultracentrifugation and chemical modification methods. Specific inhibitory effect of bovine serum albumin (Buzdygon and Leibman, JBC,259,14567,(1984)) on the allosteric binding of transducin was examined. Results:Ultracentrifugation study confirmed that transducin in solution is under equilibrium of [Tαßγ]4 and Tαßγ. Upon activation with Gpp(NH)p, these complexes dissociate into ...
Allosteric ligands of G protein-coupled receptors (GPCRs) bind to sites that are topographically distinct from the orthosteric site. AC-42 and 77-LH-28-1 are functionally selective M1 muscarinic acetylcholine (mACh) receptor allosteric agonists that are able to activate the M1 mACh receptor in the absence of an orthosteric ligand. In the present study, a variety of signalling pathways activated by AC-42 and 77-LH-28-1 have been investigated and compared with those activated by orthosteric agonists in Chinese hamster ovary (CHO) cells recombinantly expressing human M1 mACh receptors. Both orthosteric and allosteric agonists are able to activate Gαq/11-dependent signalling as demonstrated by concentration-dependent increases in [35S]-GTPγS binding to Gαq/11 subunits, [³H]-inositol phosphate accumulation and Ca²+ mobilisation. Both AC-42 and 77-LH-28-1 are also able to activate extracellular signal-regulated kinase 1/2 and cyclic AMP response-element binding protein (CREB). However, while all ...
Alcuronium allosterically increases the affinity of cardiac muscarinic receptors for methyl-N-scopolamine (NMS), whereas gallamine has the opposite effect. We discovered that strychnine also increases the affinity of muscarinic receptors in rat heart atria for NMS. It is not known whether the positive and the negative allosteric effectors bind to the same binding site. To investigate this question, we elaborated on a theoretical model predicting changes in the binding of a classic radiolabeled ligand occurring in the presence of a positive and a negative allosteric effector that compete for the allosteric binding site. The model is based on data obtained at equilibrium and avoids uncertainties associated with the use of nonequilibrium methods for the evaluation of interactions between allosteric ligands. We examined changes in the binding of [3H]NMS to membranes of rat heart atria exposed to various concentrations of a positive allosteric effector (alcuronium or strychnine) and of a negative ...
TY - JOUR. T1 - Design of allosteric hammerhead ribozymes activated by ligand-induced structure stabilization. AU - Soukup, Garrett. AU - Breaker, Ronald R.. PY - 1999/7/15. Y1 - 1999/7/15. N2 - Background: Ribozymes can function as allosteric enzymes that undergo a conformational change upon ligand binding to a site other than the active site. Although allosteric ribozymes are not known to exist in nature, nucleic acids appear to be well suited to display such advanced forms of kinetic control. Current research explores the mechanisms of allosteric ribozymes as well as the strategies and methods that can be used to create new controllable enzymes. Results: In this study, we exploit the modular nature of certain functional RNAs to engineer allosteric ribozymes that are activated by flavin mononucleotide (FMN) or theophylline. By joining an FMN- or theophylline-binding domain to a hammerhead ribozyme by different stem II elements, we have identified a minimal connective bridge comprised of a G·U ...
Chemical biology ; Sirtuin ; Sirtuin inhibitor ; Tenovins ; Allosteric ; RmlA ; QP601.5P5 ; Enzyme inhibitors ; Sirtuins ; Sirtuins--Inhibitors ; Allosteric regulation ; Nuclear magnetic resonance
The neurotransmitter glutamate and its receptors have long been of interest to scientists involved in pharmaceutical research since dysfunction of the glutamatergic signalling pathway has been associated with the pathophysiology of several psychiatric and neurological disorders. The research on AMPAR positive allosteric modulators offers opportunities to modulate fast excitatory synaptic transmission and identify new potential therapeutic agents for a range of neurodiseases. The field of AMPAR modulators continues to be a dynamic area of drug discovery with a pronounced diversification of the chemotypes explored in recent years. This article reviews literature published in this area in the last 6 years, focusing on the new core templates, some derived from high-throughput screens, with an emphasis on structure-activity relationships, drug metabolism and pharmacokinetics properties, and pharmacological profiles of these series.. ...
The alpha (2)beta (2) tryptophan synthase complex is a model enzyme for understanding allosteric regulation. We report the functional and regulatory properties of the beta S178P mutant. Ser-178 is located at the end of helix 6 of the beta subunit, belonging to the domain involved in intersubunit signaling. The carbonyl group of beta Ser-178 is hydrogen bonded to Gly-181 of loop 6 of the alpha subunit only when alpha subunit ligands are bound. An analysis by molecular modeling of the structural effects caused by the beta S178P mutation suggests that the hydrogen bond involving alpha Gly-181 is disrupted as a result of localized structural perturbations. The ratio of alpha to beta subunit concentrations was calculated to be 0.7, as for the wild type, indicating the maintenance of a tight alpha-beta complex. Both the activity of the alpha subunit and the inhibitory effect of the alpha subunit ligands indole-3-acetylglycine and D,L-alpha -glycerol-3-phosphate were found to be the same for the mutant ...
Pyruvate kinase isoform M2 (PKM2) activity is subject to complex allosteric regulation. Recently, serine and SAICAR (succinylaminoimidazolecarboxamide ribose-5′-phosphate) were identified as previously unrecognized activators of PKM2. These findings add additional complexity to how PKM2 is regulated in cells and support the notion that modulating PKM2 activity enables cells to adapt their metabolic state to specific physiological contexts.. ...
Enzymes are extremely useful and effective in many biochemical reactions but only at the right time and place. Enzyme activity is regulated in five different ways:. Allosteric control:Allosteric enzymes contain distinct regulatory sites and multiple functional sites. The protein is significantly controlled when small signal molecules bind to these regulatory sites. Also allosteric enzymes show cooperativity, which means that activity at one functional site will affect the other functional site as well.. Multiple Forms of Enzymes: Isoenzymes or Isozymes are homologous enzymes in an organism that catalyze the same reaction but are a little bit different in their structure, Km and Vmax values, and regulatory properties. Isozymes allow a reaction to be regulated at distinct locations or times.. Reversible Covalent Modification: The catalytic properties of enzymes can be altered by a covalent binding of a modifying group, most commonly to a phosphoryl group. Usually ATP will serve as a donor for ...
PRF readers can get free access to a selected Journal of Pain paper each month, thanks to the American Pain Society. Get the free full text of the selection from the November 2017 issue here.. ...
A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs. ...
SANT-2 is an inhibitor of Sonic hedgehog (Shh) signaling; antagonizes smoothened receptor activity (KD = 12 nM), which displays allosteric binding characteristics similar to SANT-1. Displaces smo-[3H]SAG-1.3 and -[3H]Cyclopamine binding (Ki values are 7.8 nM and 8.4 nM respectively). Learn More ...
Gabather has completed in vitro and in vivo experiments on the substances GT-001 - GT-006. The substances were tested in models for psychosis and anxiety, with very promising general results such as none of the substances having sedative side effects. The main focus has been on GT-002, which is generating promising results as a potential antipsychotic. In 2015 Gabather signed a research agreement with UNSW (University of New South Wales, Australia), and one of the resulting studies show that GT-002 acts as a positive allosteric modulator on the GabaA receptor. The difference from other positive allosteric modulators is that GT-002 does not affect the neuron population, which minimizes the risk of sedative or convulsive side effects. Further in-vitro studies show that GT-002 is also a highly selective substance. ...
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA Jr, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adao C, Jaramill J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2003) Gaussian 03. Gaussian, Inc., Pittsburgh, PAGoogle Scholar ...
Domain Therapeutics is developing metabotropic glutamate receptor 3 negative allosteric modulators (mGluR3 NAM) for the treatment of various cancers.
Ribbon representation of the structure of an enzyme known as ATP-PRT from TB bacteria (blue), bound to an allosteric activator (pink).
Piotr Sosnik is Former Vice Chair-Supervisory at Przedsiebiorstwo Farmaceutyczne Jelfa SA. See Piotr Sosniks compensation, career history, education, & memberships.
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Lancet, D; Licht, A; Schechter, I; and Pecht, I, "Hapten-induced allosteric transition in the light chain dimer of an immunoglobulin." (1977). Subject Strain Bibliography 1977. 708 ...
Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which has critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whe
Structural pathways are important because they provide insight into signaling mechanisms, help understand the mechanism of disease-related mutations, and assist in drug discovery. Ozbabacan et al. construct the IL-1 structural pathway and map oncogenic mutations and SNPs. They show that modeling of protein-protein interactions on a large scale can provide accurate, structural atom-level detail of signaling pathways in the human cell and help delineate the mechanism through which a mutation leads to disease.. Numerous approaches have been undertaken over the last 50 years in an effort to explain allostery. Chung-Jung Tsai and Ruth Nussinov survey points of view on allostery in a Perspective, synthesizing them via a mathematical model in order to obtain a coherent understanding of the question of how allostery works. They address this question from three standpoints: thermodynamics, free energy landscape of population shift, and structure; all with exactly the same allosteric descriptors.. ...
Concentration-dependent biphasic effects of drugs on ion channel activity have been reported in a variety of preparations, usually with stimulatory effects seen at low concentrations followed by increasingly dominant inhibition at higher levels. Such behaviour is often interpreted as evidence for the existence of separate modulatory drug binding sites. We demonstrate in this paper that it is possible for biphasic effects to be produced in an allosteric model of a ligand-activated ion channel, where diffusion-limited binding of the modulatory drug is restricted to either a stimulatory or an inhibitory site (but not both) because of steric overlap. The possibility of such an interaction mechanism should be kept in mind when interpreting experimental data if stoichiometric evidence from complementary techniques suggests that only one drug molecule is bound per receptor/ion channel complex.. ...
The report by Castro et al demonstrates that PKG activation in response to ANP activation of pGC elicits a strong feed-forward mechanism that further enhances cGMP production in the subsarcolemmal pool (Figure). The protein target of PKG that elicits this effect is unknown. Notably, this is the first feed-forward effect to be defined for cGMP signaling in any tissue. Surprisingly, it appears that there is little activation of PDE2 activity through cGMP binding to its allosteric sites, which should counter the effect, and the mechanism for terminating the feed-forward signal is not determined. Moreover, the mechanism whereby PDE2 is selectively localized to this cGMP pool is unknown.. In contrast, increased cGMP production by NO-GC elicits the opposite effect on cGMP levels by activating a negative-feedback regulation of cytosolic cGMP; this is mediated by activation of PKG, which phosphorylates and activates PDE5. The resulting increased cGMP breakdown blunts further elevation of cGMP and lowers ...
Many inhibitors affect enzyme activity • Competitive inhibition - inhibitor competes for the active sites on enzyme with the substrate • Non-competitive inhibition - inhibitor binds to an allosteric site and alters the active site configuration of the enzyme • Feedback inhibition - enzyme activity is inhibited by the end product (A enzyme-1 B enzyme-2 C enzyme-3 D) - here enzyme-1 may be inhibited by product D • Feedback inhibition regulates ATP, amino acid, numcleotide and vitamin synthesis Mechanism of enzyme action • Substrate specifically binds to the active site on the surface of the enzyme and as a consequence enzyme-substrate complex is formed - can result in change of structure of the enzyme • Substrate is transformed into product by - Rearrangement of existing atoms - Breakdown of substrate molecules - Combining with other substrate molecules • Resultant products do not fit the active site and thus are released and the enzyme site becomes free for ...
VCH-916 is a novel allosteric inhibitor of HCV NS5B polymerase. The RNA-dependent RNA polymerase (NS5B) of HCV is one of the attractive validated targets for development of new drugs to block HCV infection. VCH-916 is currently being evaluated for safety/tolerability, pharmacokinetics and anti-viral efficacy in chronically infected HCV patient ...
BICYCLIC AZA COMPOUNDS AS MUSCARINIC M1 RECEPTOR ANTAGONISTS | FATTY ACID CONJUGATES OF QUETIAPINE, PROCESS FOR MAKING AND USING THE SAME | AMINOPYRIMIDINE KINASE INHIBITORS | SUBSTITUTED 4-ALKOXYPICOLINAMIDE ANALOGS AS MGLUR5 NEGATIVE ALLOSTERIC MODULATORS AND METHODS OF MAKING AND... | NOVEL COMPOUNDS |
CXCR2 has attracted considerable attention as a potential drug target because of its involvement in different inflammatory diseases, particularly chronic pulmonary inflammatory diseases such as chronic obstructive pulmonary disease, where increased numbers of neutrophils in the sputum of patients has been shown to correlate with increased levels of IL-8 (Keatings et al., 1996; Chapman et al., 2009). As a consequence, different classes of small-molecule CXCR2 antagonists have been developed that seem to share a common mechanism of allosteric, rather than competitive inhibition (Bertini et al., 2004; Casilli et al., 2005; Garau et al., 2006; Gonsiorek et al., 2007; Moriconi et al., 2007; Nicholls et al., 2008; Bradley et al., 2009; de Kruijf et al., 2009). Allosteric inhibition is likely to be a common mechanism for drug leads arising from small-molecule screening efforts against chemokine receptors, given the large extracellular ligand-receptor interface that a competitive inhibitor must ...
Ernie Maynard asked: ,Is there a good enzyme kinetics news group out there??? ,I am interseted in allosteric interactions between proteins ,and the kinetics describing such systems Try the BTK-MCA news group (http://www.bio.net/hypermail/BTK-MCA/). Recently its been mostly advertisement and porn sites, but it isnt always like that and if you post some good messages theyll get responses. Occasionally (this month, for example) the PROTEIN-ANALYSIS news group has some relevant stuff (http://www.bio.net/hypermail/PROTEIN-ANALYSIS/9812/) Athel Email: athel at ibsm.cnrs-mrs.fr Site map: http://ir2lcb.cnrs-mrs.fr/~athel/sitemap.htm ...
A. the active site is saturated with substrate B. there is a competitive inhibitor present C. there is a non-competitive inhibitor present D. the allosteric enzyme is locked in an inactive conformation E. all substrate has been converted to product ...
A. the active site is saturated with substrate B. there is a competitive inhibitor present C. there is a non-competitive inhibitor present D. the allosteric enzyme is locked in an inactive conformation E. all substrate has been converted to product ...
Urate transport in the kidney proximal tubule is a bidirectional process. Although the urate reabsorption pathway has been elucidated recently, there is little knowledge about the excretory route. The basolateral organic anion transporters OAT1 and OAT3 presumably mediate uptake from blood into the cell, but for apical export from the cell into urine no candidate transporter has been identified. In this study, we show that the apical organic anion transporter MRP4 mediates ATP-dependent urate transport in isolated membrane vesicles and exports urate from transfected cells. Furthermore, the complex interaction pattern of urate with the MRP4 substrates MTX, cAMP, and cGMP indicates that MRP4 is an organic anion transporter with multiple allosteric binding sites.. Isolated apical and basolateral membrane vesicles from kidney proximal tubule have been used widely to study organic anion transport mechanisms, mainly using PAH or urate as a substrate (31). In contrast to basolateral membrane vesicles, ...
An electrochemical gating model is presented to account for the effects described in the companion paper by M. R. Silver, M. S. Shapiro, and T. E. DeCoursey (1994. Journal of General Physiology, 103:519-548) of Rb+ and Rb+/K+ mixtures on the kinetics and voltage dependence of an inwardly rectifying (IR) K+ channel. The model proposes that both Rb+ and K+ act as allosteric modulators of an intrinsically voltage dependent isomerization between open and closed states. Occupancy of binding sites on the outside of the channel promotes channel opening and stabilizes the open state. Rb+ binds to separate sites within the pore and plugs IR channels. Occupancy of the pore by Rb+ can modify the rates of isomerization and the affinity of the allosteric sites for activator ions. The model also incorporates the proposed triple-barreled nature of the IR channel (Matsuda, H., 1988. Journal of Physiology. 397:237-258.) by proposing that plugging of the channel is a cooperative process involving a single site in ...
University of Canterbury Library α-Isopropylmalate synthase (α-IPMS) is responsible for catalysing the first committed step in leucine biosynthesis. This pathway is found in plants and microorganisms, including pathogenic bacteria such as Mycobacterium tuberculosis and Neisseria meningitidis. α-IPMS catalyses a Claisen condensation reaction between α-ketoisovalerate (KIV) and acetyl coenzyme A (AcCoA) to form the product α-isopropylmalate (IPM). This enzyme undergoes feedback inhibition by the end product of the pathway, leucine. This regulation allows the control of the rate leucine biosynthesis. This project focuses on the α-IPMS enzymes from M. tuberculosis and N. meningitidis (MtuIPMS and NmeIPMS). These α-IPMS enzymes are homodimeric in structure. Each monomer consists of a catalytic domain which comprises of a (β/α)8 barrel fold, two subdomains and a regulatory domain, to which the allosteric binding of the natural inhibitor leucine occurs. The mechanism by which the allosteric ...
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Zhang L, Balan G, Barreiro G, Boscoe BP, Chenard LK, Cianfrogna J, Claffey MM, Chen L, Coffman KJ, Drozda SE, Dunetz JR, Fonseca KR, Galatsis P, Grimwood S, Lazzaro JT, Mancuso JY, Miller EL, Reese MR, Rogers BN, Sakurada I, Skaddan M, Smith DL, Stepan AF, Trapa P, Tuttle JB, Verhoest PR, Walker DP, Wright AS, Zaleska MM, Zasadny K, Shaffer CL. Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator. J Med Chem. 2014 Feb 13; 57(3):861-77 ...
One family, ccdAB, interferes with replication and transcription via interactions with gyrase. This family has been extensively studied in the last five years, leading to a detailed understanding on how the toxin CcdB poisons DNA-bound-gyrase and how the intrinsically disordered domain of the antitoxin CcdA is able to rejuvenated CcdB-poisoned gyrase. The latter proves to be an example on how intrinsically disordered proteins act in mechanistic terms and why intrinsic disorder is required in certain biochemical contexts.. Another family of TA modules, phd/doc, inhibit translation by interfering with the action of the ribosome. The phd/doc module of bacteriophage P1 is being used to study transcription regulation by conditional co-operativity. This is a novel regulatory mechanism used by bacteria that involves allosteric communication between two (partly) disordered protein domains. While such a form of allostery has been predicted based on theoretical arguments, our work provided the first ...
SWISS-MODEL Template Library (SMTL) entry for 6v5l.1. The HADDOCK structure model of GDP KRas in complex with its allosteric inhibitor E22
1. An allosteric enzyme. a) Is an enzyme molecule that is denatured too quickly. b) Possesses more than one active site. c) Is an enzyme molecule that binds with inhibitors only when present. d) Is an enzyme that changes shape to fit the substrate. e) Speeds up chemical reactions. 2. The number of molecules of substrates converted to product per enzyme molecule per second is called the…. a) Turnover number / kcat. b) Optimum number. c) Maximum reaction rate / Vmax. d) Michaelis-Menten Constant / Km. e) None of the above. 3. Fill in the blanks: Enzymes __________________ the free energies of reactants/products therefore ___________________ the equilibrium of the reaction.. a) Change/creating. b) Change/ increasing. c) Does not change/does not change. d) Does not change/changing. e) Increase/decreasing. 4. Which common example of an inhibitor is used as a medicinal drug?. a) Antibiotics. b) Panadol. c) Ascorbic acid. d) Aspirin. e) Lactate. 5. Enzymes act as. a) Protein molecules. b) Reaction ...
Hernán Navarro, PhD, has more than 20 years of experience in central nervous system pharmacology, with research ranging from the effects of in utero exposure to cholinomimetics on offspring brain and immune function development to the in vitro and in vivo characterization of radioligands and the pharmacological characterization of novel orthosteric or allosteric central nervous system-active compounds.
PLAN-LES-OUATES GENEVA, SWITZERLAND--(Marketwire - February 23, 2011) - Addex Pharmaceuticals / Addex Pharmaceuticals 2010 Financial Results Processed and transmitted by Thomson Reuters. The issuer is solely responsible for the content of this announcement. Geneva, Switzerland, 23 February 2011 - Allosteric modulation company Addex Pharmaceuticals (SWISS: ADXN) announced today 2010 financial...
TY - JOUR. T1 - Differences in the allosteric properties of pure low and high phosphate forms of phosphofructokinase from rat liver.. AU - Sakakibara, R.. AU - Uyeda, K.. PY - 1983/7/25. Y1 - 1983/7/25. N2 - Low phosphate and high phosphate forms of phosphofructokinase (Furuya, E., and Uyeda, K. (1980) J. Biol. Chem. 255, 11656-11659) from rat liver were purified to homogeneity and various properties were compared. The specific activities of these enzymes and their electrophoretic mobilities on polyacrylamide in sodium dodecyl sulfate are the same. A limited tryptic digestion yields products with no change in the enzyme activity but with a reduction in the molecular weight of about 2000. Both low and high phosphate enzymes can be phosphorylated by the catalytic subunit of cAMP-dependent protein kinase, and approximately twice as much [32P]phosphate is incorporated into the low phosphate than the high phosphate enzyme. A comparison of their allosteric kinetic properties reveal that the high ...
Allosteric inhibition of coagulation enzymes offers the advantage of controlled inhibition. In this study, a small library of mono sulfated indole and benzothiazole based molecules was synthesized and screened against the panel of coagulation proteases. The results reveal that selected molecules inhibit the thrombin, factor Xa and factor XIa with moderate potency. Compound 6a was found to have an allosteric mode of inhibition against thrombin. Plasma clotting assays suggest that selected inhibitors 14b, 14c and 14d prolong both prothrombin and activated partial thromboplastin time. Overall, this work presents the newer class of allosteric inhibitors of thrombin and factor XIa with improved aqueous solubility profile.. KEYWORDS: Anticoagulation; Factor XIa; Sulfation; Thrombin. ...
Integrating LC-MS/MS molecular networking and bioassay-guided fractionation enabled the targeted isolation of a new and bioactive cyclic octapeptide, samoamide A (1), from a sample of cf. Symploca sp. collected in American Samoa. The structure of 1 was established by detailed 1D and 2D NMR experiments, HRESIMS data, and chemical degradation/chromatographic (e.g., Marfeys analysis) studies. Pure compound 1 was shown to have in vitro cytotoxic activity against several human cancer cell lines in both traditional cell culture and zone inhibition bioassays. Although there was no particular selectivity between the cell lines tested for samoamide A, the most potent activity was observed against H460 human non-small-cell lung cancer cells (IC50 = 1.1 mu M). Molecular modeling studies suggested that one possible mechanism of action for 1 is the inhibition of the enzyme dipeptidyl peptidase (CD26, DPP4) at a reported allosteric binding site, which could lead to many downstream pharmacological effects. ...
Our lab is interested in the biology and therapeutic potential of targeting Class C G protein-coupled receptors (GPCRs). We are predominantly focussed on two class members: metabotropic glutamate receptor subtype 5 (mGlu5) and the calcium-sensing receptor (CaSR). mGlu5 is an exciting new target for schizophrenia, Alzheimers disease, autism spectrum disorders and depression, whereas modulators of the CaSR are already in the clinic for hyperparathyroidism and are putative therapeutics for osteoporosis, calcium handling disorders, asthma and idiopathic pulmonary arterial hypertension. We are pursuing a novel class of therapeutics, called allosteric modulators, to selectively target these receptors. To facilitate rational drug design and discovery efforts, a better understanding of the functional consequences and structural basis of allosteric modulation is needed.. Available projects examine ...
Glycine receptors (GlyRs) are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs) have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA) are positive modulators of α(1), α(2) and α(3) GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly) potentiate α(1) GlyRs but inhibit α(2) and α(3). This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM) region 2 and intracellular lysine 385 determine ...
The main objective when analyzing equilibrium data are to identify elements that respond to external forces, and to quantify their interactions with the catalytic unit, which in ion channels is the conducting pore. Quaternary descriptions of enzyme function have been useful in studying regulatory proteins-most notably hemoglobin, widely considered the poster child of protein allosteric theory. Modeling hemoglobin using sophisticated variants of the classical Monod-Wyman-Changeux (MWC) equation (Monod et al., 1965) has achieved impressive insight into its allosteric machinery (Eaton et al., 2007). A K+ channel whose regulation, at a basic level, is formulaically similar to that of hemoglobin (though mechanistically distinct), is the large-conductance voltage- and Ca2+-dependent (BK) channel. The BK channel derives its voltage dependence from four voltage-sensing (J) domains located within the membrane electric field, and also to a small degree from the pore (L) itself. Calcium sensors (K) are ...
Thrombin demonstrates a high level of allosteric regulation.[2] Allosterism in thrombin is regulated by the exosites 1 and 2 and the sodium binding site. A recent patent review has shown that the general consensus among researchers is that allosteric inhibitors may provide a more regulatable anticoagulant.[3] Some of the allosteric inhibitors discovered include DNA aptamers,[3] benzofuran dimers,[4] benzofuran trimers,[5] as well as polymeric lignins.[6] A new sulfated β-O4 lignin (SbO4L) has been discovered which has shown a dual mechanism of action for anti-thrombosis. This SbO4L shows allosteric inhibition of thrombin for fibrinogen, while providing a competitive inhibition of thrombin interaction with platelet glycoprotein Ibα (GPIbα), thereby preventing thrombin mediated platelet aggregation.[7] However, despite the growing interest and the advances in allosterism, no allosteric thrombin inhibitor has yet reached the stage of clinical trials.. ...
Cys-loop ligand-gated ion channels mediate rapid neurotransmission throughout the central nervous system. They possess agonist recognition sites and allosteric sites where modulators regulate ion channel function. Using strychnine-sensitive glycine receptors, we identified a scaffold of hydrophobic residues enabling allosteric communication between glycine-agonist binding loops A and D, and the Zn2+-inhibition site. Mutating these hydrophobic residues disrupted Zn2+ inhibition, generating novel Zn2+-activated receptors and spontaneous channel activity. Homology modeling and electrophysiology revealed that these phenomena are caused by disruption to three residues on the - loop face of the Zn2+-inhibition site, and to D84 and D86, on a neighboring beta3 strand, forming a Zn2+-activation site. We provide a new view for the activation of a Cys-loop receptor where, following agonist binding, the hydrophobic core and interfacial loops reorganize in a concerted fashion to induce downstream ...
1. 1. Pyruvate kinase of the adductor muscle of the sea mussel displays an absolute requirement for Mg2+ or Mn2+. By the use of Ca2+ or Zn2+ no enzyme activity is obtained. 2. 2. In the presence of Mn2+, in contrast to Mg2+, always hyperbolic substrate saturation curves are obtained. 3. 3. ... read more There is evidence that Mn2+ not only acts by forming an ADP-Mn2+ complex, but also as an allosteric activator. 4. 4. Ca2+ is a strong inhibitor but the enzyme becomes less sensitive to this inhibition when Mg2+ is replaced for Mn2. show less ...

Allosteric Site Inhibitors for Caspases | Science SignalingAllosteric Site Inhibitors for Caspases | Science Signaling

J. A. Hardy, J. Lam, J. T. Nguyen, T. OBrien, J. A. Wells, Discovery of an allosteric site in the caspases. Proc. Natl. Acad. ... Hardy et al. report the application of a method called "Tethering" to identify an allosteric site inhibitor on the executioner ... Thus, the authors speculate that this domain may serve as an allosteric site for an as yet unidentified native regulator. ... Your Name) thought you would like to see this page from the Science Signaling web site. ...
more infohttps://stke.sciencemag.org/content/2004/248/tw306

Allosteric site legal definition of allosteric siteAllosteric site legal definition of allosteric site

What is allosteric site? Meaning of allosteric site as a legal term. What does allosteric site mean in law? ... Definition of allosteric site in the Legal Dictionary - by Free online English dictionary and encyclopedia. ... Allosteric site legal definition of allosteric site https://legal-dictionary.thefreedictionary.com/allosteric+site ... Related to allosteric site: competitive inhibition site. noun address, base, environs, habitat, locale, location, neighborhood ...
more infohttps://legal-dictionary.thefreedictionary.com/allosteric+site

Propofol Inhibits SIRT2 Deacetylase through a Conformation-specific, Allosteric SitePropofol Inhibits SIRT2 Deacetylase through a Conformation-specific, Allosteric Site

Despite the allosteric nature of this site, three residues that line the propofol site (Ile169, Asp170, and Thr171) also line ... allosteric protein site that is unique from the previously described binding sites of other inhibitors. This suggests that ... that are located in a single allosteric protein site, and propofol inhibited [3H]AziPm photolabeling of this site in myelin ... Propofol Inhibits SIRT2 Deacetylase through a Conformation-specific, Allosteric Site* Brian P. Weiserठand Roderic G. ...
more infohttp://pubmedcentralcanada.ca/pmcc/articles/PMC4375505/

Allosteric sites | definition of allosteric sites by Medical dictionaryAllosteric sites | definition of allosteric sites by Medical dictionary

... allosteric sites explanation free. What is allosteric sites? Meaning of allosteric sites medical term. What does allosteric ... Looking for online definition of allosteric sites in the Medical Dictionary? ... allosteric sites. allosteric sites. [al′ōster′ik] Etymology: Gk, allos + stereos, solid ... to assume that allosteric modulators and allosteric activators are subtype-specific because allosteric sites are not the sites ...
more infohttps://medical-dictionary.thefreedictionary.com/allosteric+sites

Turning a protein kinase on or off from a single allosteric site via disulfide trapping | PNASTurning a protein kinase on or off from a single allosteric site via disulfide trapping | PNAS

... but has not yet been applied to kinase allosteric sites.. Here, we use disulfide trapping to target an allosteric site on the ... studies show that disulfide trapping is useful for characterizing allosteric sites on kinases and that a single allosteric site ... produced both agonists and antagonists at the same site (4, 5). It is intriguing that a single allosteric site on a kinase, the ... Turning a protein kinase on or off from a single allosteric site via disulfide trapping. Jack D. Sadowsky, Mark A. Burlingame, ...
more infohttps://www.pnas.org/content/108/15/6056?with-ds=yes

Turning a protein kinase on or off from a single allosteric site via disulfide trapping | PNASTurning a protein kinase on or off from a single allosteric site via disulfide trapping | PNAS

... but has not yet been applied to kinase allosteric sites.. Here, we use disulfide trapping to target an allosteric site on the ... studies show that disulfide trapping is useful for characterizing allosteric sites on kinases and that a single allosteric site ... produced both agonists and antagonists at the same site (4, 5). It is intriguing that a single allosteric site on a kinase, the ... Turning a protein kinase on or off from a single allosteric site via disulfide trapping. Jack D. Sadowsky, Mark A. Burlingame, ...
more infohttps://www.pnas.org/content/108/15/6056?ijkey=25a53031c0dfb06e23864a32a62e52b7ff64aa52&keytype2=tf_ipsecsha

L0710ap - committed step in a pathway Allosteric regulation(mechanism Binding of ATP to a non-substrate(allosteric site on the...L0710ap - committed step in a pathway Allosteric regulation(mechanism Binding of ATP to a non-substrate(allosteric site on the...

committed step in a pathway Allosteric regulation (mechanism) Binding of ATP to a non-substrate (allosteric) site on the enzyme ... allosteric) site on the enzyme causes a conformational change that converts the enzyme from an active to an inactive form. ADP ... L0710ap - committed step in a pathway Allosteric.... This preview shows document pages 1 - 27. Sign up to view the full ... Unformatted text preview: committed step in a pathway Allosteric regulation (mechanism) Binding of ATP to a non-substrate ( ...
more infohttps://www.coursehero.com/file/6123813/L0710ap/

Amiloride derivatives and a non-peptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing...Amiloride derivatives and a non-peptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing...

Amiloride derivatives and a non-peptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing ... Amiloride derivatives and a non-peptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing ... Amiloride derivatives and a non-peptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing ... Amiloride derivatives and a non-peptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing ...
more infohttp://molpharm.aspetjournals.org/content/early/2008/03/14/mol.107.043521

The Allosteric Binding Sites of Sulfotransferase 1A1 | Drug Metabolism & DispositionThe Allosteric Binding Sites of Sulfotransferase 1A1 | Drug Metabolism & Disposition

The Allosteric Binding Sites of Sulfotransferase 1A1. Ian Cook, Ting Wang, Charles N. Falany and Thomas S. Leyh ... SULT1A1 Allosteric Binding Sites. Ian Cook, Ting Wang, Charles N. Falany and Thomas S. Leyh ... SULT1A1 Allosteric Binding Sites. Ian Cook, Ting Wang, Charles N. Falany and Thomas S. Leyh ... The Allosteric Binding Sites of Sulfotransferase 1A1 Message Subject (Your Name) has forwarded a page to you from Drug ...
more infohttp://dmd.aspetjournals.org/content/43/3/418/tab-article-info

Mechanistic insights into the active site and allosteric communication pathways in human nonmuscle myosin-2C | eLifeMechanistic insights into the active site and allosteric communication pathways in human nonmuscle myosin-2C | eLife

... that connects the converter at the distal end of the myosin motor domain via the relay helix with switch-2 of the active site. ... R788 is part of an allosteric communication pathway ... Allosteric communication pathway between the active site and ... Proposed allosteric communication pathway from the converter to the NM2C active site.. (A) Residue R788 connects the converter ... R788 is part of a conserved pathway that connects the active site and the converter. R788 is part of an allosteric ...
more infohttps://elifesciences.org/articles/32742

Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors | IRIS...Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors | IRIS...

Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors. ... Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors ... To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB2R. Radioligand and non-radioactive ... we confirmed that CBD does not bind with high affinity to the orthosteric site of the human CB2R where the synthetic ...
more infohttps://iris.unife.it/handle/11392/2382282

BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF...BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF...

BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF- ... BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF- ... A binding model is proposed in which BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then affects the ... active sites of the subunits differently. BMS-345541 was also shown to have excellent pharmacokinetics in mice, and peroral ...
more infohttps://scholars.duke.edu/display/pub1293122

Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the alpha 7 nicotinic...Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the alpha 7 nicotinic...

One allosteric site is surface-exposed and is located near the N-terminal alpha-helix of the extracellular domain. Ligand ... Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the alpha 7 nicotinic ... This work presents a structural framework for different allosteric binding sites in the alpha 7 nAChR and paves the way for ... A third site is located at a pocket right below the agonist binding site. Using electrophysiological recordings on the human a7 ...
more infohttp://uu.diva-portal.org/smash/record.jsf?pid=diva2:827034

Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors<...Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors<...

Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors. ... Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors. ... The NCA-bindlng site for BAs overlaps both the phencyclidine- and dizocilpine-binding sites in the desensitized Torpedo nAChR ... The NCA-bindlng site for BAs overlaps both the phencyclidine- and dizocilpine-binding sites in the desensitized Torpedo nAChR ...
more infohttps://scholars.okstate.edu/en/publications/interaction-of-benzylidene-anabaseine-analogues-with-agonist-and-

AID 1054287 - Displacement of [33P]S1P from S1P3 receptor allosteric binding site (unknown origin) expressed in CHO cells after...AID 1054287 - Displacement of [33P]S1P from S1P3 receptor allosteric binding site (unknown origin) expressed in CHO cells after...

S1P from S1P3 receptor allosteric binding site (unknown origin) expressed in CHO cells after 30 mins by scintillation counting ...
more infohttps://pubchem.ncbi.nlm.nih.gov/bioassay/1054287

Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2 |...Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2 |...

Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2. David J ... Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2. David J ... Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2. David J ... Identification of a Putative Intracellular Allosteric Antagonist Binding-Site in the CXC Chemokine Receptors 1 and 2 ...
more infohttp://molpharm.aspetjournals.org/content/early/2008/08/19/mol.107.044610

Common Internal Allosteric Network Links Anesthetic Binding Sites in a Pentameric Ligand-Gated Ion ChannelCommon Internal Allosteric Network Links Anesthetic Binding Sites in a Pentameric Ligand-Gated Ion Channel

... correlation analysis to describe the internal allosteric network underlying the coupling of ligand and distant effector sites ... Overall, the results suggest that the same allosteric network may underlie the actions of various anesthetics, regardless of ... and that propofol also localizes to an extracellular region shared with the crystallographic ketamine binding site. Subsequent ...
more infohttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158795

In silico
 mapping of allosteric ligand binding sites in type-1 cannabinoid receptorIn silico mapping of allosteric ligand binding sites in type-1 cannabinoid receptor

In silico mapping of allosteric ligand binding sites in type-1 cannabinoid receptor. Annalaura Sabatucci, Daniel Tortolani, ...
more infohttps://www.growkudos.com/publications/10.1002%25252Fbab.1589/reader

Practical Fragments: Novel Assay (SPR) Leads to Novel Allosteric Binding Site (nAChR)Practical Fragments: Novel Assay (SPR) Leads to Novel Allosteric Binding Site (nAChR)

It is important to note that most of these drugs work through an allosteric site distant from the agonist binding site. Most ... Figure 2. Allosteric Binding Sites. This is a really nice piece of work. I think the SPR assay is really clever and I would ... There is little information on structural implications at allosteric sites. The authors decided to address this unmet need with ... allows detection of fragments not competing for binding to the orthosteric site and were therefore potential allosteric ligands ...
more infohttp://practicalfragments.blogspot.com/2015/07/novel-assay-spr-leads-to-novel.html

If a gaseous mixture is made of 2.41gof He and 2.79gof | bartlebyIf a gaseous mixture is made of 2.41gof He and 2.79gof | bartleby

The site on an enzyme molecule that does the catalytic work is called the: a. binding site. b. allosteric site..... Chemistry ... Use rise web to look up the percentage of dopant for a commercially available p-type semiconductor. Imagine tha.... Chemistry ...
more infohttps://www.bartleby.com/solution-answer/chapter-13-problem-67qap-introductory-chemistry-a-foundation-9th-edition/9781337399425/if-a-gaseous-mixture-is-made-of-241gof-he-and-279gof-ne-in-an-evacuated-104lcontainer-at-25c/ed571ee6-252d-11e9-8385-02ee952b546e

Reuptake inhibitor - WikipediaReuptake inhibitor - Wikipedia

Allosteric site transporter substrates[edit]. Alternatively, some reuptake inhibitors bind to allosteric sites and inhibit ... Notably, this allosteric site may be directly related to the above-mentioned PCP binding sites.[15][20] ... Instead of binding to the active site on the serotonin transporter, they bind to an allosteric site, which exerts its effects ... 1994). "PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site". Neurotoxicol Teratol. 16 (4): 343-353. doi: ...
more infohttps://en.wikipedia.org/wiki/Non-selective_monoamine_reuptake_inhibitors

MacOdrum Library - Carletons Institutional Repository:
  An osmotic-remedial, temperature-sensitive mutation in the allosteric...MacOdrum Library - Carleton's Institutional Repository: An osmotic-remedial, temperature-sensitive mutation in the allosteric...

Conserved amino acids at the active site and the allosteric activity sites are also evident. An unusual feature of the ... This substitution appears to disrupt proper folding of the allosteric activity site during synthesis of the protein. ... An osmotic-remedial, temperature-sensitive mutation in the allosteric activity site of ribonucleotide reductase in Neurospora ... temperature-sensitive mutation in the allosteric activity site of ribonucleotide reductase in Neurospora crassa. MGG Molecular ...
more infohttps://ir.library.carleton.ca/pub/16411

Computational fragment-based drug design to explore the hydrophobic subpocket of the mitotic kinesin Eg5 allosteric binding...Computational fragment-based drug design to explore the hydrophobic subpocket of the mitotic kinesin Eg5 allosteric binding...

Web of Science, CrossRef and Altmetric. Citations. Single number count for article citations from each services database may ... The citations counts are reliant on the availability of the individual APIs from Web of Science and CrossRef. These counts are ... fragment-based drug design to explore the hydrophobic subpocket of the mitotic kinesin Eg5 allosteric binding site. Last ...
more infohttps://jcheminf.biomedcentral.com/articles/10.1186/1758-2946-2-S1-P29/metrics

Frontiers | Non-nucleotide Agonists Triggering P2X7 Receptor Activation and Pore Formation | PharmacologyFrontiers | Non-nucleotide Agonists Triggering P2X7 Receptor Activation and Pore Formation | Pharmacology

... possibly a positive allosteric P2X7R modulator, b) the bactericidal peptide LL-37, c) the amyloidogenic β peptide, and d) serum ... the intriguing question of how these different non-nucleotide ligands may co-operate with ATP at inflammatory or tumor sites. ... possibly a positive allosteric P2X7R modulator, b) the bactericidal peptide LL-37, c) the amyloidogenic β peptide, and d) serum ... the intriguing question of how these different non-nucleotide ligands may co-operate with ATP at inflammatory or tumor sites. ...
more infohttps://www.frontiersin.org/articles/10.3389/fphar.2018.00039/full
  • A second site is located in the vestibule of the receptor, in a preexisting intrasubunit pocket opposite the agonist binding site and corresponds to a previously identified site involved in positive allosteric modulation of the bacterial homolog ELIC. (diva-portal.org)
  • Other structurally unrelated agents have been reported to activate the P2X7R via a poorly understood mechanism of action: (a) the antibiotic polymyxin B, possibly a positive allosteric P2X7R modulator, (b) the bactericidal peptide LL-37, (c) the amyloidogenic β peptide, and (d) serum amyloid A. Some agents, such as Alu-RNA, have been suggested to activate the P2X7R acting on the intracellular N- or C-terminal domains. (frontiersin.org)
  • Here, we apply a site-directed technology, disulfide trapping, to interrogate structurally and functionally how an allosteric site on the Ser/Thr kinase, 3-phosphoinositide-dependent kinase 1 (PDK1)-the PDK1-interacting-fragment (PIF) pocket-is engaged by an activating peptide motif on downstream substrate kinases (PIFtides) and by small molecule fragments. (pnas.org)
  • These studies show that disulfide trapping is useful for characterizing allosteric sites on kinases and that a single allosteric site on a protein kinase can be exploited for both activation and inhibition by small molecules. (pnas.org)
  • Prior to initiating HTS campaigns, it would be beneficial to have a simple method that permits directed interrogation of kinase allosteric sites with small compounds and facile assessment of the effects of binding on protein structure and function. (pnas.org)
  • Because the approach is site-directed, disulfide trapping has proven valuable as a tool to validate known, suspected, and orphan allosteric sites on protein surfaces as small molecule targets ( 3 - 6 ), but has not yet been applied to kinase allosteric sites. (pnas.org)
  • Here, we use disulfide trapping to target an allosteric site on the surface of 3-phosphoinositide-dependent kinase 1 (PDK1)-the so-called PDK1-interacting fragment (PIF) pocket. (pnas.org)
  • BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. (duke.edu)
  • We found that clinical concentrations of propofol inhibit this enzymatic function of SIRT2, and we characterized the allosteric protein site that propofol binds. (pubmedcentralcanada.ca)
  • In PKA, PKB, and PKC the site analogous to the PIF pocket binds to a specific hydrophobic motif (HM) at the C terminus of these kinases ( 7 ). (pnas.org)
  • We used disulfide trapping to ( i ) better elucidate how a PIFtide binds to and activates PDK1, ( ii ) identify new small molecule fragments targeting the PIF pocket, and ( iii ) begin to characterize their allosteric mechanism. (pnas.org)
  • A binding model is proposed in which BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then affects the active sites of the subunits differently. (duke.edu)
  • A third site is located at a pocket right below the agonist binding site. (diva-portal.org)
  • Experimental approach: Functional and radioligand-binding assays were used to examine the interaction of two BA analogues, 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) and Its primary metabolite 3-(4-hydroxy-2-methoxybenzylidene)anabaseine (4OH-DMXBA) with both agonist and non-competitive antagonist (NCA)-bindlng sites on muscle-type nAChRs. (okstate.edu)
  • 3 H]Nlcotine competition-binding experiments confirmed that 40H-DMXBA has higher affinity than DMXBA for the agonist sites, and that DMXBA Is also a competitive antagonist. (okstate.edu)
  • It is important to note that most of these drugs work through an allosteric site distant from the agonist binding site. (blogspot.com)
  • However, scattered evidence generated over the last several years suggests that ATP might not be the only agonist, especially at inflammatory sites. (frontiersin.org)
  • To distinguish allosteric binders from competitive binders using SPR spectroscopy we perfused each fragment alone (green triangle) or in combination with the competitive antagonist d-tubocurarine (black circle). (blogspot.com)
  • In the case of an allosteric binder, the response units observed for the mixture of fragment + d-tubocurarine is close to the sum of fragment alone + d-tubocurarine alone (blue dashed line). (blogspot.com)
  • C) In the case of a competitive binder, the response units for the mixture of fragment + d-tubocurarine is lower than the sum of fragment alone + d-tubocurarine alone because both compounds compete for binding at the same site. (blogspot.com)
  • D) Example traces for fragment 4, which was identified as one of the allosteric binders in this study. (blogspot.com)
  • To assist in the identification of propofol targets and binding sites, photoactive analogs that retain anesthetic efficacy have been developed by our group and others ( 7 , - 10 ). (pubmedcentralcanada.ca)
  • I think the SPR assay is really clever and I would expect that many people will now be taking a similar approach to discovering allosteric sites in their targets. (blogspot.com)
  • Myosin-2 phylogeny, overall topology, and active site characteristics of human NM2C. (elifesciences.org)
  • The region shown in orange corresponds to the active site and the junction of U50 kDa and L50 kDa. (elifesciences.org)
  • Based on kinetic data, it has previously been reported that hEST may contain an allosteric site (Zhang et al. (thefreedictionary.com)
  • These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function. (ox.ac.uk)
  • report the application of a method called "Tethering" to identify an allosteric site inhibitor on the executioner caspases, caspase-3. (sciencemag.org)
  • One allosteric site is surface-exposed and is located near the N-terminal alpha-helix of the extracellular domain. (diva-portal.org)