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)

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 ...
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 ...
Positive allosteric modulators (PAMs), also known as allosteric enhancers or potentiators, induce an amplification of the effect of receptors response to the primary ligand without directly activating the receptor.[2][3] Benzodiazepines principally act as PAMs at the GABAA receptor.[4]. Negative allosteric modulators (NAMs) act at an allosteric site to reduce the responsiveness of the receptor to the endogenous ligand.[3] Ro15-4513 is a NAM at the α1β2γ2 GABAA receptor[citation needed].[nb 1]. Silent allosteric modulators (SAMs), also called neutral or null modulators, occupy the allosteric binding site and behave functionally neutral. Flumazenil can be regarded as such an example. The modulatory activity can be first-order, second-order, or both. Second-order modulators alter the modulatory activity of first-order modulators, whereas first-order modulators do not alter the activity of other allosteric modulators.[citation needed] (−)‐Epigallocatechin‐3‐gallate is one such example of ...
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 ...
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.
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 ...
VCP171 is an AR positive allosteric modulator. VCP171 elicited positive allosteric effects on the binding affinity of orthosteric agonists at both the rat and human A1 -receptors that showed clear probe dependence.
TY - JOUR. T1 - Positive and negative cooperativities at subsequent steps of oxygenation regulate the allosteric behavior of multistate sebacylhemoglobin. AU - Bucci, Enrico. AU - Razynska, Anna. AU - Kwansa, Herman. AU - Gryczynski, Zygmunt. AU - Collins, John H.. AU - Fronticelli, Clara. AU - Unger, Ron. AU - Braxenthaler, Michael. AU - Moult, John. AU - Ji, Xinhua. AU - Gilliland, Gary. PY - 1996/3/19. Y1 - 1996/3/19. N2 - Cross-linked human hemoglobin (HbA) is obtained by reaction with bis(3,5- dibromosalicyl) sebacate. Peptide maps and crystallographic analyses confirm the presence of the 10 carbon atom long sebacyl residue cross-linking the two β82 lysines of the β-cleft (DecHb). The Adairs constants, obtained from the oxygen binding isotherms, show that at the first step of oxygenation normal hemoglobin and DecHb have a very similar oxygen affinity. In DecHb negative binding cooperativity is present at the second step of oxygenation, which has an affinity 27 times lower than at the ...
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 ...
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 ...
Adenylyl cyclases and the interaction between calcium and cAMP signalling. Spanning binding sites on allosteric proteins with polymer-linked ligand dimers
DAVID A. FELL; A Correction to Webers Description of Ligand Binding by Allosteric Proteins. Biochem Soc Trans 1 December 1978; 6 (6): 1264-1266. doi: https://doi.org/10.1042/bst0061264. Download citation file:. ...
BioAssay record AID 676852 submitted by ChEMBL: Negative allosteric modulation of human mGluR5 expressed in HEK293A cells assessed as inhibition of glutamate-induced calcium flux by FLIPR method.
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
Nature Chemical Biology, Published online: 02 December 2019; doi:10.1038/s41589-019-0407-2 A computational approach for designing GPCRs with new signaling functions including...
OpenLink Virtuoso version 07.20.3232 as of Jan 24 2020, on Linux (x86_64-generic-linux-glibc25), Single-Server Edition (61 GB total memory ...
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...
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.
1. An allosteric interaction occurs when the binding of a ligand to its site on a receptor is able to modify the binding of another ligand to a topographically ...
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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allosteric regulation is a common mechanism used by the complex biomolecular systems for regulatory activities and adaptability in a mobile environment, serving as an effective. ...
allosteric regulation is a common mechanism used by the complex biomolecular systems for regulatory activities and adaptability in a mobile environment, serving as an effective. ...
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, adenylate 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. An example of cAMPs function is 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 beside the lac promoter, making it easier for RNA polymerase to bind to the adjacent promoter to start transcription ...
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 ...
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 ...
It is informative to calculate the ratio of binding affinities for pairs of different ternary complexes, because it reveals how allosteric couplings between sites vary with ligand and coregulator peptide identity. The free energy of binding a coregulator peptide to a GR-ligand complex is given by ΔG = ΔGP + ΔgLP + ΔgLA + ΔgbP. It follows that the difference in ΔG between two different GR-ligand complexes is ΔΔG = −RT ln[Ka(Lm, Pi)/Ka(Ln, Pi)] = ΔΔgLP + ΔΔgLA. However, the minor variation in pm (i.e., the relative population of active helix 12 conformations detected by NMR) between the different ternary complexes indicates that the variation ΔΔgLA contributes relatively little to variations in coregulator-binding affinity (fig. S5), which instead is dominated by ΔΔgLP. Thus, the SPR results can be interpreted to extract differences between ligands in their strength of allosteric coupling to coregulator binding, ΔΔgLP.. Comparing complexes with different ligands but the same ...
TY - JOUR. T1 - Structural elements and allosteric mechanisms governing regulation and catalysis of CSK-family kinases and their inhibition of Src-family kinases. AU - Ia, Kim K.. AU - Mills, Ryan D.. AU - Hossain, Mohammed I.. AU - Chan, Khai Chew. AU - Jarasrassamee, Boonyarin. AU - Jorissen, Robert. AU - Cheng, Heung Chin. PY - 2010/10/1. Y1 - 2010/10/1. N2 - C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are endogenous inhibitors constraining the activity of the oncogenic Src-family kinases (SFKs) in cells. Both kinases suppress SFKs by selectively phosphorylating their consensus C-terminal regulatory tyrosine. In addition to phosphorylation, CHK can suppress SFKs by a unique non-catalytic inhibitory mechanism that involves tight binding of CHK to SFKs to form stable complexes. In this review, we discuss how allosteric regulators, phosphorylation, and inter-domain interactions interplay to govern the activity of CSK and CHK and their ability to inhibit SFKs. In particular, based ...
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.
Journal Article: Allosteric Activation of Bacterial Swi2/Snf2 (Switch/Sucrose Non-fermentable) Protein RapA by RNA Polymerase: BIOCHEMICAL AND STRUCTURAL STUDIES ...
View and buy high purity VU 0424465 from Tocris Bioscience. Potent mGlu5 positive allosteric modulator and agonist; binds allosteric site with high affinity.
Gain a perfect MCAT score! This medical chemistry course covers all essentials: carbapenems ✓, creation of prodrugs ✓, allosteric binding ✓, amino acids ✓, preparation of amines ✓. Learn online with high-yield video lectures & earn perfect scores. Save time & study efficiently. ➨ Try now for free!
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: ...
There are no known allosteric regulatory sites. Like all other cytochrome P450s, cholesterol-24 hydroxylase utilizes an ... The active site is accessed via a single entrance created by two helices (B' and F) and the β1-sheet. ... A single cholesterol molecule takes up the entirety of the active site, with the aliphatic tail of the cholesterol held in ... Binding of cholesterol results in an enzymatic conformational change and a subsequent induced fit of the active site around the ...
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 ...
"Characterization of the CHK1 allosteric inhibitor binding site." Biochemistry 48.41 (2009): 9823-9830". "Ardiani, Andressa, et ...
The CB1 receptor possesses an allosteric modulatory binding site. The CB1 receptor is a pre-synaptic heteroreceptor that ... Effects may vary based on the site of cannabinoid application, input from higher cortical centers, and whether drug application ... Nguyen T, Li JX, Thomas BF, Wiley JL, Kenakin TP, Zhang Y (November 2016). "Allosteric Modulation: An Alternate Approach ... Navarro HA, Howard JL, Pollard GT, Carroll FI (April 2009). "Positive allosteric modulation of the human cannabinoid (CB) ...
... 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 ...
Allosteric regulation is the binding of an effector to a site on the protein other than the active site, causing a ... FBP binds to the allosteric binding site on domain C of pyruvate kinase and changes the conformation of the enzyme, causing the ... "The Allosteric Regulation of Pyruvate Kinase A SITE-DIRECTED MUTAGENESIS STUDY". Journal of Biological Chemistry. 275 (24): ... Due to the allosteric inhibitory effects of ATP on pyruvate kinase, a decrease in ATP results in diminished inhibition and the ...
"Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site". Proceedings of the National ... PNU-120596 is a drug that acts as a potent and selective positive allosteric modulator for the α7 subtype of neural nicotinic ... Barron, S.; Mclaughlin, J.; See, J.; Richards, V.; Rosenberg, R. (2009). "An allosteric modulator of alpha7 nicotinic receptors ... "A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo ...
"Characterization of the allosteric anion-binding site of O-acetylserine sulfhydrylase". Biochemistry. 40 (25): 7446-52. doi: ...
Usenik A, Legiša M (23 November 2010). "Evolution of allosteric citrate binding sites on 6-phosphofructo-1-kinase". PLOS ONE. 5 ... In particular, the binding site for the PFK inhibitor citrate is found in the PFKL C-terminal region. This gene encodes one of ... N-terminal of the subunits carries out their catalytic activity while the C-terminal contains allosteric ligand binding sites. ... Abnormal splicing of the muscle phosphofructokinase gene due to a point mutation at the 5'-splice site". The Journal of ...
... allosteric site,allosteric site]]. A receptor's agonist does not bind to its allosteric binding site. The binding of a non- ... If the non-competitive antagonist binds to the allosteric site and an agonist binds to the ligand site, the receptor will ... non-competitive antagonists can either bind to the ligand site or other site called the [ ... A competitive antagonist will attach itself to the same binding site of the receptor that the agonist will bind to. Even though ...
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 ...
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 ...
Allosteric activators such as AMP and ADP bind to the allosteric site as to facilitate the formation of the R state by inducing ... On the opposite side of the each subunit from each active site is the allosteric site, at the interface between subunits in the ... binding site as well as a separate allosteric binding site. Each subunit of the tetramer is 319 amino acids and consists of two ... "Evolution of allosteric citrate binding sites on 6-phosphofructo-1-kinase". PLOS ONE. 5 (11): 677-683. doi:10.1371/journal.pone ...
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 ...
... drug discovery targeting allosteric sites". Journal of Medicinal Chemistry. 57 (18): 7485-7498. doi:10.1021/jm5011786. PMC ...
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. ...
"Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site". Protein Sci. 13 (1): 155-65. doi:10.1110/ps ... The four CBS domains create two binding sites for AMP commonly referred to as Bateman domains. Binding of one AMP to a Bateman ... of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it ...
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 ...
This protein may use the morpheein model of allosteric regulation. Site-specific recombinase technology Masuda, Takao (2011-01- ... Retroviral INs are not to be confused with phage integrases, such as λ phage integrase (Int) (see site-specific recombination ... Both reactions are catalysed by the same active site and occur via transesterification, without a covalent protein-DNA ... intermediate, in contrast to reactions catalysed by Ser and Tyr recombinases (see site specific recombination). HIV integrase ...
ATP competes with AMP for the allosteric effector site on the PFK enzyme. ATP concentrations in cells are much higher than ... Thus, the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in ... since it is one of the irreversible steps and has key allosteric effectors, AMP and fructose 2,6-bisphosphate (F2,6BP). ...
Inhibition may also occur via binding to an external allosteric polyamine binding site. Subunit composition of iGluRs heavily ... "Allosteric inhibition of nicotinic acetylcholine receptors of vertebrates and insects by philanthotoxin". Journal of ...
However, there may be unoccupied allosteric binding sites that may be of interest. Furthermore, it may be that only apoprotein ... Binding site identification is the first step in structure based design. If the structure of the target or a sufficiently ... In brief, binding site identification usually relies on identification of concave surfaces on the protein that can accommodate ... Yuan Y, Pei J, Lai L (Dec 2013). "Binding site detection and druggability prediction of protein targets for structure-based ...
A common drug, diazepam, acts as an allosteric enhancer at this binding site. Another receptor for GABA, known as GABAB, can be ... This GABAA receptor contains many binding sites that allow conformational changes and are the primary target for drug ... The most common of these binding sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. ... Sigel, E (2002). "Mapping of the benzodiazepine recognition site on GABA(A) receptors". Current Topics in Medicinal Chemistry. ...
This allosteric, conformational change interferes with the ability of the active site of sAC to adequately bind ATP to convert ... Bithionol is the first known sAC inhibitor to act through the bicarbonate binding site via a mostly allosteric mechanism. ... Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site. Journal of ... The Arginine 176 usually interacts with the ATP and other catalytic ions at the active site, so when it turns from its normal ...
Sarcosine; Polyamine site agonists: Neomycin. *Spermidine. *Spermine; Other positive allosteric modulators: 24S- ... By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia® is a registered trademark of the Wikimedia ...
α2 houses the active site for nucleotide reduction and the binding sites for allosteric effectors (E). β2 contains the ... α2 houses the active site for nucleotide reduction and the binding sites for allosteric effectors (E). β2 contains the ... α2 houses the active site for nucleotide reduction and the binding sites for allosteric effectors (E). β2 contains the ... α2 houses the active site for nucleotide reduction and the binding sites for allosteric effectors (E). β2 contains the ...
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. ...
... Adv Pharmacol. 2015;72:53-96. doi: 10.1016/bs.apha. ... Keywords: Allosteric modulation; GABA(A) receptor structure; Ligand-binding sites; Pharmacology; Receptor subtype-selective ... Some of these sites have been identified by mutagenesis, photolabeling, and docking studies. For most of these ligands, however ... binding sites are not known. Due to the high flexibility of GABAA receptors and the existence of multiple drug-binding sites, ...
... 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, ...
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 ...
... 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 ...
... 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 ...
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 ...
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. ...
A Potential Site of Allosteric Modulation David J. J. Waugh, Robert J. Gaivin, Derek S. Damron, Paul A. Murray and Dianne M. ... A Potential Site of Allosteric Modulation David J. J. Waugh, Robert J. Gaivin, Derek S. Damron, Paul A. Murray and Dianne M. ... A Potential Site of Allosteric Modulation David J. J. Waugh, Robert J. Gaivin, Derek S. Damron, Paul A. Murray and Dianne M. ... Binding, Partial Agonism, and Potentiation of α1-Adrenergic Receptor Function by Benzodiazepines: A Potential Site of ...
Although the binding site for the agonist is by definition an allosteric site, by convention it is called the orthosteric site ... Thus, a site that plays a purely structural role in nature can be co-opted as an allosteric site in pharmacology; in agreement ... If a second allosteric site exists, ligands that bind there can act as positive or negative allosteric modulators (PAMs or NAMs ... Although some allosteric sites may host naturally occurring regulatory molecules (e.g., the glycine binding site of the N- ...
Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors ... Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors ... Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors ... Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors ...
... 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 ...
Propofol is an allosteric agonist with multiple binding sites on concatemeric ternary GABAA receptors. Daniel J Shin, Allison L ... Propofol is an allosteric agonist with multiple binding sites on concatemeric ternary GABAA receptors. Daniel J Shin, Allison L ... Propofol is an allosteric agonist with multiple binding sites on concatemeric ternary GABAA receptors. Daniel J Shin, Allison L ... Utility of an "allosteric site-impaired" M2 muscarinic acetylcholine receptor as a novel construct for validating mechanisms of ...
Allosteric Changes of the Deoxyribonucleic Acid-Binding Site of lac Repressor from Escherichia coli. KONRAD BEYREUTHER ... Allosteric Changes of the Deoxyribonucleic Acid-Binding Site of lac Repressor from Escherichia coli ... Allosteric Changes of the Deoxyribonucleic Acid-Binding Site of lac Repressor from Escherichia coli ... Allosteric Changes of the Deoxyribonucleic Acid-Binding Site of lac Repressor from Escherichia coli ...
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 ...
Structural basis for allosteric cross-talk between the asymmetric nucleotide binding sites of a heterodimeric ABC exporter ... Nucleotide binding at the degenerate site results in structural rearrangements, which are transmitted to the consensus site via ... Nucleotide binding at the degenerate site results in structural rearrangements, which are transmitted to the consensus site via ... Structural basis for allosteric cross-talk between the asymmetric nucleotide binding sites of a heterodimeric ABC exporter. ...
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 ( ...
Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release. / Scott, John W ... Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release. Chemistry and ... title = "Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release", ... T1 - Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release ...
The redox‐regulated SoxR protein acts from a single DNA site as a repressor and an allosteric activator. Elena Hidalgo, ... This website is best viewed using the latest versions of all modern web browsers. Older browsers may not display correctly. ...
In silico mapping of allosteric ligand binding sites in type-1 cannabinoid receptor. Annalaura Sabatucci, Daniel Tortolani, ...
S1P from S1P3 receptor allosteric binding site (unknown origin) expressed in CHO cells after 30 mins by scintillation counting ...
Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic acetylcholine M2 ... Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic acetylcholine M2 ... Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic acetylcholine M2 ... title = "Three allosteric modulators act at a common site, distinct from that of competitive antagonists, at muscarinic ...
Unassigned densities near the gate and surrounding the scaffold domain, may represent potential allosteric binding sites, which ... gates the extracellular access to the substrate-binding site. However, it has remained unclear how substrate binding and ... We thus predict that these sites are potential allosteric binding sites that might affect the dynamics of the transport cycle. ... Potential allosteric binding sites. In the cryo-EM maps of the inward-open states of ASCT2C467R, an additional density is ...
  • 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)
  • An allosteric modulator can also preserve the activity of the endogenous ligand. (news-medical.net)
  • Crystallographic studies revealed that 'MetRS02' compounds bind to an allosteric pocket in L. major MetRS not previously described and enzymatic studies demonstrated a non-competitive mode of inhibition. (dundee.ac.uk)
  • ATP is an allosteric activator of aspartate transcarbamolyase because it stabilizes the R-state of ATCase, effecting neighboring subunits by making it easier for substrate to bind.The increase of the concentration of ATP has two potential explanations. (wikibooks.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)
  • This provides a comprehensive druggability analysis of potential allosteric sites in all kinases. (bu.edu)
  • Although the binding site for the agonist is by definition an allosteric site, by convention it is called the orthosteric site to distinguish it from other possible binding sites. (aspetjournals.org)
  • A third site is located at a pocket right below the agonist binding site. (diva-portal.org)
  • The binding of substrate to the binding site requires at least three contact points in order to achieve stereo-, regio-, and enantioselectivity. (wikipedia.org)
  • It is important to note that most of these drugs work through an allosteric site distant from the agonist binding site. (blogspot.com)
  • It is almost buried inside the binding site. (intechopen.com)
  • This is in line with the assumption that the galantamine binding site is at the junction of these two amino acid stretches. (intechopen.com)
  • 1) The acetylcholine dissociates from its extracellular binding site, a process that is enhanced by rapid cleavage of the neurotransmitter by the acetylcholine esterase in the synaptic cleft. (intechopen.com)
  • The extracellular domain contains the binding site for the neurotransmitter acetylcholine (ACh). (intechopen.com)
  • Models of T. gondii TS/TS interface binding site. (nih.gov)
  • Identification of an Allosteric Binding Site for RORyt Inhibition. (eurekalert.org)
  • Urate shifted cGMP transport by MRP4 from positive cooperativity ( K m and V max value of 180 ± 20 μM and 58 ± 4 pmol·mg −1 ·min −1 , respectively, Hill coefficient of 1.4 ± 0.1) to single binding site kinetics ( K m and V max value of 2.2 ± 0.9 mM and 280 ± 50 pmol·mg −1 ·min −1 , respectively). (physiology.org)
  • Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8 and 10, directly blocking serotonin binding. (rcsb.org)
  • Type IV inhibitors bind to allosteric sites far removed from the ATP binding site. (news-medical.net)
  • The α1β2γ2 subtype is of particular interest in this context because it comprises the major benzodiazepine binding site in the brain. (jneurosci.org)
  • The goal of this work was to identify the binding site of ORG27569 at CB 1 . (pubmedcentralcanada.ca)
  • To this end, we used computation, synthesis, mutation, and functional studies to identify the ORG27569-binding site in the CB 1 TMH3-6-7 region. (pubmedcentralcanada.ca)
  • This site is consistent with the results of K3.28 192 A, F3.36 200 A, W5.43 279 A, W6.48 356 A, and F3.25 189 A mutation studies, which revealed the ORG27569-binding site overlaps with our previously determined binding site of SR141716A but extends extracellularly. (pubmedcentralcanada.ca)
  • In this work, we conducted structural, functional and computational studies on a zebrafish PIP5Ka variant with a mutation at the same site. (msu.edu)
  • 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)
  • Despite a substantial sequence identity and a highly conserved actomyosin ATPase cycle, structural and allosteric adaptations causative for the tremendous enzymatic and hence physiological differences are largely unknown ( Figure 1A ) ( Heissler and Sellers, 2016 , 2013 ). (elifesciences.org)
  • Nucleotide binding at the degenerate site results in structural rearrangements, which are transmitted to the consensus site via two D-loops located at the NBD interface. (uzh.ch)
  • There is little information on structural implications at allosteric sites. (blogspot.com)
  • The amino acids T197 and K143 are possible binding sites for galantamine (Gal), as predicted by docking studies. (intechopen.com)
  • One of these mutations results in a non-conservative amino acid substitution within the four-helix bundle that is important in the allosteric control of ribonucleotide reductase activity. (carleton.ca)