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)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. Weiser‡§ and Roderic G. ...
... Howard, R. J. Stockholm Univ, ...
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 ...
- The existence of multiple GABAA receptor subtypes with distinct subunit composition, the contribution of distinct subunit sequences to binding sites of different receptor subtypes, as well as the observation that even subunits not directly contributing to a binding site are able to influence affinity and efficacy of drugs, contribute to a unique pharmacology of each GABAA receptor subtype. (nih.gov)
- This chimeric receptor was used to conduct an innovative fragment-library screening in combination with X-ray crystallography to identify allosteric binding sites. (diva-portal.org)
- Using electrophysiological recordings on the human a7 nAChR we demonstrate that the identified fragments, which bind at these sites, can modulate receptor activation. (diva-portal.org)
- The data could be reconciled with a model involving a ternary complex between (1) the receptor, (2) carbachol, N- methylscopolamine or atropine acting at the orthosteric binding site and (3) C 7 /3'-phth, alcuronium or gallamine acting at a common, allosteric site with varying degrees of heterotropic cooperativity. (monash.edu)
- INTRODUCTION: Two recent models are in use for analysis of allosteric drug action at receptor sites remote from orthosteric binding sites. (biomedsearch.com)
- Therefore, this receptor family serves as an excellent example for demonstrating the suitability of site-directed mutagenesis for investigating receptor function and exploring drug action. (intechopen.com)
- These drugs all work using the same mechanism: they bind to a receptor at the same site as its natural ligand and thereby influence its behavior. (eurekalert.org)
- For the first time in fifty years, research has identified an effective means for drugs to bind to a novel site on a nuclear receptor and thus inhibit it, explains Luc Brunsveld, TU/e professor of Chemical Biology. (eurekalert.org)
- The alpha-2A adrenergic receptor normally works this way -- it has a binding site for the neurotransmitter norepinephrine, and that binding activates a signaling process that mobilizes the brain and body for action. (eurekalert.org)
- The UAB researchers found that amyloid-beta oligomers bind to a separate site on the alpha-2A adrenergic receptor, distinct from the site for norepinephrine binding. (eurekalert.org)
- Here, we identify and explore the allosteric communication network within the glucocorticoid receptor (GR) ligand-binding domain (LBD). (sciencemag.org)
- Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. (nih.gov)
- The existence of allosteric sites on receptor molecules has expanded potential drug mechanisms. (news-medical.net)
- Allosteric binding sites are distinct from the orthosteric binding site, and they allow for many different ligand-receptor interactions beyond those controlled by the orthosteric site. (news-medical.net)
- An ago-allosteric ligand mediates a receptor response in the absence of an orthosteric ligand, while also potentiating the receptor in the presence of an orthosteric ligand. (news-medical.net)
- Thus, it is able to target both orthosteric and allosteric binding sites on a single receptor. (news-medical.net)
- At this allosteric site, ORG27569 promotes an intermediate conformation of the CB 1 receptor, explaining ORG27569's ability to increase equilibrium binding of CP55,940. (pubmedcentralcanada.ca)
- 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)
- Unassigned densities near the gate and surrounding the scaffold domain, may represent potential allosteric binding sites, which could guide the design of lipidic-inhibitors for anticancer therapy. (nature.com)
- Ligand binding at this site causes a conformational change of the alpha-helix as the fragment wedges between the alpha-helix and a loop homologous to the main immunogenic region of the muscle alpha 1 subunit. (diva-portal.org)
- By contrast, the D-loop of the consensus site is flexible and the aspartate to alanine mutation and conformational restriction by cross-linking strongly reduces ATP hydrolysis and substrate transport. (uzh.ch)
- Instead of binding to the active site on the serotonin transporter , they bind to an allosteric site, which exerts its effects by causing conformational changes in the transporter protein and thereby modulating the affinity of substrates for the active site. (wikipedia.org)
- Amino acids at the binding site of ubiquitin generally follow the induced fit model, whereas the rest of the protein generally adheres to conformational selection. (wikipedia.org)
- Ligand-binding induces conformational changes in the ligand binding site which are coupled to the ion opening. (blogspot.com)
- Allosteric sites allow effectors to bind to the protein, often resulting in a conformational change involving protein dynamics. (wikipedia.org)
- Allostery involves coupling of ligand binding at one site with a conformational or dynamic change at a distant site, thereby affecting binding at that site. (sciencemag.org)
- A conformational change within the serpin interrupts the cleavage reaction, deforming the protease active site and preventing dissociation. (portlandpress.com)
- 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)
- report the application of a method called "Tethering" to identify an allosteric site inhibitor on the executioner caspases, caspase-3. (sciencemag.org)
- As a result, escitalopram has been marketed as an allosteric serotonin reuptake inhibitor . (wikipedia.org)
- Our computational investigation of the nicotinamide adenine diphosphate hydride (NADH)/adenosine diphosphate (ADP) site presented in this paper provides insight into the opposite allosteric effects induced at a single site of binding inhibitor NADH versus activator ADP to GDH. (utmb.edu)
- C) Cartoon representation of the allosteric site with the inhibitor in the center. (nih.gov)
- Crystallographic analysis of a hydroxylated polychlorinated biphenyl (OH-PCB) bound to the catalytic estrogen binding site of human estrogen sulfotransferase. (thefreedictionary.com)
- The active site consists of amino acid residues that form temporary bonds with the substrate ( binding site ) and residues that catalyse a reaction of that substrate (catalytic site). (wikipedia.org)
- Binding sites in blue, catalytic site in red and peptidoglycan substrate in black. (wikipedia.org)
- This is evidence that ATCase has distinct regulatory and catalytic sites. (wikibooks.org)
- There are 2 substrate-binding sites: the catalytic A site, and the non-catalytic B site that may play a role in the transfer of substrate or product between the active site and the solvent. (uniprot.org)
- 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)
- In combination with integrated mutagenesis, ensemble-solution kinetics, and molecular dynamics simulation approaches, the structure reveals an allosteric communication pathway that connects the distal end of the motor domain with the active site. (elifesciences.org)
- L0710ap - committed step in a pathway Allosteric. (coursehero.com)
- The allosteric free energy responds to variations in ligand structure: subtle changes gradually tune allostery while preserving the transmission pathway, whereas substitution of the entire pharmacophore leads to divergent allosteric control by apparently rewiring the communication network. (sciencemag.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)
- metabolism: Fine control: …the regulatory sites are termed allosteric sites. (britannica.com)
- This is in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site. (wikipedia.org)
- It has been suggested that this article be merged with Regulatory site . (wikipedia.org)
- CTP inhibits ATCase by binding to the regulatory sites stabilizing the T-state. (wikibooks.org)
- We conclude that propofol inhibits the mammalian deacetylase SIRT2 through a conformation-specific, allosteric protein site that is unique from the previously described binding sites of other inhibitors. (pubmedcentralcanada.ca)
- In its lead inflammation program, Locus has created exquisitely selective p38 inhibitors which bind to p38 at an allosteric site and do not involve the ATP site. (thefreedictionary.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)
- Each active site is evolved to be optimised to bind a particular substrate and catalyse a particular reaction, resulting in high specificity . (wikipedia.org)
- This specificity is determined by the arrangement of amino acids within the active site and the structure of the substrates. (wikipedia.org)
- Initially, the interaction between the active site and the substrate is non-covalent and transient. (wikipedia.org)
- : 148 The charge distribution on the substrate and active site must be complementary, which means all positive and negative charges must be cancelled out. (wikipedia.org)
- The active site usually contains non-polar amino acids, although sometimes polar amino acids may also occur. (wikipedia.org)
- A tighter fit between an active site and the substrate molecule is believed to increase the efficiency of a reaction. (wikipedia.org)
- If the tightness between the active site of DNA polymerase and its substrate is increased, the fidelity, which means the correct rate of DNA replication will also increase. (wikipedia.org)
- In general, when a subunit randomly collides with a molecule of substrate , the active site, in essence, forms a glove around its substrate. (wikipedia.org)
- Conserved amino acids at the active site and the allosteric activity sites are also evident. (carleton.ca)
- Moving Beyond Active-Site Detection: MixMD Applied to Allosteric Systems. (ebi.ac.uk)
- An enzyme's activity can be altered by covalently attaching a different group to its active site. (wikibooks.org)
- It blocks the natural substrate from binding to the active site. (wikibooks.org)
- Once substrate S leaves active site substrate T can bind and react with the newly modified active site. (wikibooks.org)
- reversible binding, active site. (studystack.com)
- Structural networks of intramolecular communication between the RAS active site and membrane-interacting regions on the G-domain are disrupted in oncogenic mutants. (aacrjournals.org)
- The focus is on the active site with the P-loop, switch I, and switch II labeled in Roman type. (aacrjournals.org)
- Active site inhibitors 3. (slideserve.com)
- Allostery refers to the binding of a metabolite at a site other than the chemically active site of a protein. (news-medical.net)
- C, the active site in the Ras/RasGAP complex (PDB code 1WQ1). (aacrjournals.org)
- D, the active site for intrinsic hydrolysis in Ras. (aacrjournals.org)
- I have to put my fingers right here in the active site. (brightstorm.com)
- 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)
- They have greater selectivity than the orthosteric site as they bind under less evolutionary pressure. (news-medical.net)
- The NCA-bindlng site for BAs overlaps both the phencyclidine- and dizocilpine-binding sites in the desensitized Torpedo nAChR ion channel. (okstate.edu)
- 300 Da) that could either activate or inhibit PDK1 by conjugation to the PIF pocket, thus displaying greater functional diversity than is displayed by PIFtides conjugated to the same sites. (pnas.org)
- Alternatively, some reuptake inhibitors bind to allosteric sites and inhibit reuptake indirectly and noncompetitively . (wikipedia.org)
- 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)
- The models are valid in pharmacology, enzymology, transportology as well as several other fields of biology involving allosteric concentration effects. (biomedsearch.com)
- KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe. (ox.ac.uk)
- Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors. (monash.edu)
- 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)