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.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.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Glucose-1-Phosphate Adenylyltransferase: An ATP-dependent enzyme that catalyzes the addition of ADP to alpha-D-glucose 1-phosphate to form ADP-glucose and diphosphate. The reaction is the rate-limiting reaction in prokaryotic GLYCOGEN and plant STARCH biosynthesis.Kinetics: The rate dynamics in chemical or physical systems.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).Pyruvate Kinase: ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Protein Structure, Quaternary: The characteristic 3-dimensional shape and arrangement of multimeric proteins (aggregates of more than one polypeptide chain).Crystallography, X-Ray: The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)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.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.Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.Ribonucleotide ReductasesAmino 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.Glyceric AcidsMolecular 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.Bithionol: Halogenated anti-infective agent that is used against trematode and cestode infestations.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.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)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 Multimerization: The assembly of the QUATERNARY PROTEIN STRUCTURE of multimeric proteins (MULTIPROTEIN COMPLEXES) from their composite PROTEIN SUBUNITS.Chorismate Mutase: An isomerase that catalyzes the conversion of chorismic acid to prephenic acid. EC 5.4.99.5.Fructosediphosphates: Diphosphoric acid esters of fructose. The fructose-1,6- diphosphate isomer is most prevalent. It is an important intermediate in the glycolysis process.Glutamate Dehydrogenase: An enzyme that catalyzes the conversion of L-glutamate and water to 2-oxoglutarate and NH3 in the presence of NAD+. (From Enzyme Nomenclature, 1992) EC 1.4.1.2.Glycerol Kinase: An enzyme that catalyzes the formation of glycerol 3-phosphate from ATP and glycerol. Dihydroxyacetone and L-glyceraldehyde can also act as acceptors; UTP and, in the case of the yeast enzyme, ITP and GTP can act as donors. It provides a way for glycerol derived from fats or glycerides to enter the glycolytic pathway. EC 2.7.1.30.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.Uridine Monophosphate: 5'-Uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2', 3' or 5' position.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.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.Protein Subunits: Single chains of amino acids that are the units of multimeric PROTEINS. Multimeric proteins can be composed of identical or non-identical subunits. One or more monomeric subunits may compose a protomer which itself is a subunit structure of a larger assembly.Adenosine Monophosphate: Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position.Phosphofructokinase-1: An allosteric enzyme that regulates glycolysis by catalyzing the transfer of a phosphate group from ATP to fructose-6-phosphate to yield fructose-1,6-bisphosphate. D-tagatose- 6-phosphate and sedoheptulose-7-phosphate also are acceptors. UTP, CTP, and ITP also are donors. In human phosphofructokinase-1, three types of subunits have been identified. They are PHOSPHOFRUCTOKINASE-1, MUSCLE TYPE; PHOSPHOFRUCTOKINASE-1, LIVER TYPE; and PHOSPHOFRUCTOKINASE-1, TYPE C; found in platelets, brain, and other tissues.Molecular Dynamics Simulation: A computer simulation developed to study the motion of molecules over a period of time.Amino Acids, Aromatic: Amino acids containing an aromatic side chain.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.Dimerization: The process by which two molecules of the same chemical composition form a condensation product or polymer.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.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)Catalysis: The facilitation of a chemical reaction by material (catalyst) that is not consumed by the reaction.Nucleotidyltransferases: A class of enzymes that transfers nucleotidyl residues. EC 2.7.7.Phosphoglycerate Dehydrogenase: An enzyme that catalyzes the oxidation of 3-phosphoglycerate to 3-phosphohydroxypyruvate. It takes part in the L-SERINE biosynthesis pathway.Biocatalysis: The facilitation of biochemical reactions with the aid of naturally occurring catalysts such as ENZYMES.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.Adenosine Diphosphate: Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position.Thermodynamics: A rigorously mathematical analysis of energy relationships (heat, work, temperature, and equilibrium). It describes systems whose states are determined by thermal parameters, such as temperature, in addition to mechanical and electromagnetic parameters. (From Hawley's Condensed Chemical Dictionary, 12th 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.Molecular Conformation: The characteristic three-dimensional shape of a molecule.Recombinant Proteins: Proteins prepared by recombinant DNA technology.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.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.Escherichia coli Proteins: Proteins obtained from ESCHERICHIA COLI.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)Bacterial Proteins: Proteins found in any species of bacterium.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.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.Hemoglobins: The oxygen-carrying proteins of ERYTHROCYTES. They are found in all vertebrates and some invertebrates. The number of globin subunits in the hemoglobin quaternary structure differs between species. Structures range from monomeric to a variety of multimeric arrangements.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)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.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.Phosphoenolpyruvate Sugar Phosphotransferase System: The bacterial sugar phosphotransferase system (PTS) that catalyzes the transfer of the phosphoryl group from phosphoenolpyruvate to its sugar substrates (the PTS sugars) concomitant with the translocation of these sugars across the bacterial membrane. The phosphorylation of a given sugar requires four proteins, two general proteins, Enzyme I and HPr and a pair of sugar-specific proteins designated as the Enzyme II complex. The PTS has also been implicated in the induction of synthesis of some catabolic enzyme systems required for the utilization of sugars that are not substrates of the PTS as well as the regulation of the activity of ADENYLYL CYCLASES. EC 2.7.1.-.Protein Engineering: Procedures by which protein structure and function are changed or created in vitro by altering existing or synthesizing new structural genes that direct the synthesis of proteins with sought-after properties. Such procedures may include the design of MOLECULAR MODELS of proteins using COMPUTER GRAPHICS or other molecular modeling techniques; site-specific mutagenesis (MUTAGENESIS, SITE-SPECIFIC) of existing genes; and DIRECTED MOLECULAR EVOLUTION techniques to create new genes.Enzyme Stability: The extent to which an enzyme retains its structural conformation or its activity when subjected to storage, isolation, and purification or various other physical or chemical manipulations, including proteolytic enzymes and heat.Guanosine Triphosphate: Guanosine 5'-(tetrahydrogen triphosphate). A guanine nucleotide containing three phosphate groups esterified to the sugar moiety.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.GlycogenAspartic Acid: One of the non-essential amino acids commonly occurring in the L-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter.Histidine: An essential amino acid that is required for the production of HISTAMINE.Oxygen: An element with atomic symbol O, atomic number 8, and atomic weight [15.99903; 15.99977]. It is the most abundant element on earth and essential for respiration.Glycogen Synthase: An enzyme that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains. EC 2.4.1.11.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.Ion Channel Gating: The opening and closing of ion channels due to a stimulus. The stimulus can be a change in membrane potential (voltage-gated), drugs or chemical transmitters (ligand-gated), or a mechanical deformation. Gating is thought to involve conformational changes of the ion channel which alters selective permeability.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.Peptides: Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are linear polypeptides that are normally synthesized on RIBOSOMES.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Spectrometry, Fluorescence: Measurement of the intensity and quality of fluorescence.Protein Folding: Processes involved in the formation of TERTIARY PROTEIN STRUCTURE.Proteins: Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.Macromolecular Substances: Compounds and molecular complexes that consist of very large numbers of atoms and are generally over 500 kDa in size. In biological systems macromolecular substances usually can be visualized using ELECTRON MICROSCOPY and are distinguished from ORGANELLES by the lack of a membrane structure.Cloning, Molecular: The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.Temperature: The property of objects that determines the direction of heat flow when they are placed in direct thermal contact. The temperature is the energy of microscopic motions (vibrational and translational) of the particles of atoms.Cell Line: Established cell cultures that have the potential to propagate indefinitely.N-Methylscopolamine: A muscarinic antagonist used to study binding characteristics of muscarinic cholinergic receptors.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.Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.

Allosteric regulation of even-skipped repression activity by phosphorylation. (1/3161)

The Drosophila homeodomain protein Even-skipped (Eve) is a well characterized transcriptional repressor. Here, we show that Eve's ability to function in vitro is negatively regulated by phosphorylation. DNA-binding activity was unaffected by phosphorylation, but phosphorylated Eve was unable to interact with the TATA-binding protein (TBP), a known target for repression. Unexpectedly, phosphorylation of the Eve N terminus, which is dispensable for repression and TBP binding, was necessary and sufficient to inactivate Eve. LiCl, which specifically inhibits glycogen synthase kinase-3 (GSK-3), reduced Eve phosphorylation in nuclear extract and blocked inhibition of repression. In addition, Eve was phosphorylated and inactivated by purified GSK-3 beta plus casein kinase II. Our results suggest a novel mechanism of transcriptional control involving phosphorylation-induced allosteric interference with a repressive protein-protein interaction.  (+info)

Regulation of AMP deaminase from chicken erythrocytes. A kinetic study of the allosteric interactions. (2/3161)

The allosteric properties of AMP deaminase [EC 3.5.4.6] from chicken erythrocytes have been qualitatively and quantitatively accounted for by the concerted transition theory of Monod et al., on the assumption that this enzyme has different numbers of binding sites for each ligand. Theoretical curves yield a satisfactory fit for all experimental saturation functions with respect to activation by alkali metals and inhibition by Pi, assuming that the numbers of binding sites for AMP, alkali metals, and Pi are 4, 2, and 4, respectively. The enzyme was inhibited by concentrations of ATP and GTP below 0.1 and 0.25 mM, respectively, whereas activation of the enzyme was observed at ATP and GTP concentrations above 0.4 and 1.5 mM, respectively. These unusual kinetics with respect to ATP and GTP could be also accounted for by assuming 2 inhibitory and 4 activating sites for each ligand.  (+info)

An allosteric synthetic DNA. (3/3161)

Allosteric DNA oligonucleotides are potentially useful diagnostic reagents. Here we develop a model system for the study of allosteric interactions in DNAs. A DNA that binds either Cibacron blue or cholic acid was isolated and partially characterized. Isolation was performed using a multi-stage SELEX. First, short oligos that bind either Cibacron blue or cholic acid were enriched from random oligonucleotide pools. Then, members of the two pools were fused to form longer oligos, which were then selected for theability to bind Cibacron blue columns and elute with cholic acid. One resulting isolate (A22) was studied. Dye- and cholate-binding functions can be separated on sequences from the 5'- and 3'-regions, respectively. Ligand-column affinity assays indicate that each domain binds only its respective ligand. However, the full-length A22 will bind either dye or cholate columns and elute with the other ligand, as if binding by the ligands is mutually exclusive. Furthermore, S1 nuclease protection assays show that Cibacron blue causes a structural change in A22 and that cholic acid inhibits this change. This system will be useful for elucidating mechanisms of allosteric interactions in synthetic DNAs.  (+info)

Heterotropic effectors exert more significant strain on monoligated than on unligated hemoglobin. (4/3161)

The effect of allosteric effectors, such as inositol hexakisphosphate and/or bezafibrate, has been investigated on the unliganded human adult hemoglobin both spectroscopically (employing electronic absorption, circular dichroism, resonance Raman, and x-ray absorption near-edge spectroscopies) and functionally (following the kinetics of the first CO binding step up to a final 4% ligand saturation degree). All data indicate that the unliganded T-state is not perturbed by the interaction with either one or both effectors, suggesting that their functional influence is only exerted when a ligand molecule is bound to the heme. This is confirmed by the observation that CO dissociation from partially liganded hemoglobin ( +info)

Dual allosteric modulation of pacemaker (f) channels by cAMP and voltage in rabbit SA node. (5/3161)

1. A Monod-Whyman-Changeux (MWC) allosteric reaction model was used in the attempt to describe the dual activation of 'pacemaker' f-channel gating subunits by voltage hyperpolarization and cyclic nucleotides. Whole-channel kinetics were described by assuming that channels are composed of two identical subunits gated independently according to the Hodgkin-Huxley (HH) equations. 2. The simple assumption that cAMP binding favours open channels was found to readily explain induction of depolarizing voltage shifts of open probability with a sigmoidal dependence on agonist concentration. 3. Voltage shifts of open probability were measured against cAMP concentration in macropatches of sino-atrial (SA) node cells; model fitting of dose-response relations yielded dissociation constants of 0.0732 and 0.4192 microM for cAMP binding to open and closed channels, respectively. The allosteric model correctly predicted the modification of the pacemaker current (If) time constant curve induced by 10 microM cAMP (13.7 mV depolarizing shift). 4. cAMP shifted deactivation more than activation rate constant curves, according to sigmoidal dose-response relations (maximal shifts of +22.3 and +13.4 mV at 10 microM cAMP, respectively); this feature was fully accounted for by allosteric interactions, and indicated that cAMP acts primarily by 'locking' f-channels in the open configuration. 5. These results provide an interpretation of the dual voltage- and cyclic nucleotide- dependence of f-channel activation.  (+info)

Coupling of the oxygen-linked interaction energy for inositol hexakisphosphate and bezafibrate binding to human HbA0. (6/3161)

The energetics of signal propagation between different functional domains (i.e. the binding sites for O2, inositol hexakisphospate (IHP), and bezafibrate (BZF)) of human HbA0 was analyzed at different heme ligation states and through the use of a stable, partially heme ligated intermediate. Present data allow three main conclusions to be drawn, and namely: (i) IHP and BZF enhance each others binding as the oxygenation proceeds, the coupling free energy going from close to zero in the deoxy state to -3.4 kJ/mol in the oxygenated form; (ii) the simultaneous presence of IHP and BZF stabilizes the hemoglobin T quaternary structure at very low O2 pressures, but as oxygenation proceeds it does not impair the transition toward the R structure, which indeed occurs also under these conditions; (iii) under room air pressure (i.e. pO2 = 150 torr), IHP and BZF together induce the formation of an asymmetric dioxygenated hemoglobin tetramer, whose features appear reminiscent of those suggested for transition state species (i.e. T- and R-like tertiary conformation(s) within a quaternary R-like structure).  (+info)

Allosteric control of three B12-dependent (class II) ribonucleotide reductases. Implications for the evolution of ribonucleotide reduction. (7/3161)

Three separate classes of ribonucleotide reductases are known, each with a distinct protein structure. One common feature of all enzymes is that a single protein generates each of the four deoxyribonucleotides. Class I and III enzymes contain an allosteric substrate specificity site capable of binding effectors (ATP or various deoxyribonucleoside triphosphates) that direct enzyme specificity. Some (but not all) enzymes contain a second allosteric site that binds only ATP or dATP. Binding of dATP to this site inhibits the activity of these enzymes. X-ray crystallography has localized the two sites within the structure of the Escherichia coli class I enzyme and identified effector-binding amino acids. Here, we have studied the regulation of three class II enzymes, one from the archaebacterium Thermoplasma acidophilum and two from eubacteria (Lactobacillus leichmannii and Thermotoga maritima). Each enzyme has an allosteric site that binds ATP or various deoxyribonucleoside triphosphates and that regulates its substrate specificity according to the same rules as for class I and III enzymes. dATP does not inhibit enzyme activity, suggesting the absence of a second active allosteric site. For the L. leichmannii and T. maritima enzymes, binding experiments also indicate the presence of only one allosteric site. Their primary sequences suggest that these enzymes lack the structural requirements for a second site. In contrast, the T. acidophilum enzyme binds dATP at two separate sites, and its sequence contains putative effector-binding amino acids for a second site. The presence of a second site without apparent physiological function leads to the hypothesis that a functional site was present early during the evolution of ribonucleotide reductases, but that its function was lost from the T. acidophilum enzyme. The other two B12 enzymes lost not only the function, but also the structural basis for the site. Also a large subgroup (Ib) of class I enzymes, but none of the investigated class III enzymes, has lost this site. This is further indirect evidence that class II and I enzymes may have arisen by divergent evolution from class III enzymes.  (+info)

Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase. (8/3161)

Phosphoribosylpyrophosphate (PRPP) synthetase (PRS) superactivity is an X-linked disorder characterized by gout with overproduction of purine nucleotides and uric acid. Study of the two X-linked PRS isoforms (PRS1 and PRS2) in cells from certain affected individuals has shown selectively increased concentrations of structurally normal PRS1 transcript and isoform, suggesting that this form of the disorder involves pretranslational dysregulation of PRPS1 expression and might be more appropriately termed overactivity of normal PRS. We applied Southern and Northern blot analyses and slot blotting of nuclear runoffs to delineate the process underlying aberrant PRPS1 expression in fibroblasts and lymphoblasts from patients with overactivity of normal PRS. Neither PRPS1 amplification nor altered stability or processing of PRS1 mRNA was identified, but PRPS1 transcription was increased relative to GAPDH (3- to 4-fold normal in fibroblasts; 1.9- to 2.4-fold in lymphoblasts) and PRPS2. Nearly coordinate relative increases in each process mediating transfer of genetic information from PRPS1 transcription to maximal PRS1 isoform expression in patient fibroblasts further supported the idea that accelerated PRPS1 transcription is the major aberration leading to PRS1 overexpression. In addition, modulated relative increases in PRS activities at suboptimal Pi concentration and in rates of PRPP and purine nucleotide synthesis in intact patient fibroblasts indicate that despite an intact allosteric mechanism of regulation of PRS activity, PRPS1 transcription is a major determinant of PRPP and purine synthesis. The genetic basis of disordered PRPS1 transcription remains unresolved; normal- and patient-derived PRPS1s share nucleotide sequence identity at least 850 base pairs 5' to the consensus transcription initiation site.  (+info)

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 ...
P2X7 is an ATP-gated ion channel that is highly expressed by leukocytes, such as macrophages. Here, it has been demonstrated to be involved in the regulation of various cell death pathways; including apoptosis, pyroptosis, necrosis, and autophagy. However, cell death induction via P2X7 is complex and is reliant upon the nature of the stimulus, the duration of the stimulus, and the cell type investigated. Previous reports state that high extracellular ATP concentrations promote osmotic lysis, but whether positive allosteric modulation of P2X7 in the presence of lower concentrations of ATP condemns cells to the same fate is unknown. In this study, we compared cell death induced by high ATP concentrations, to cell death induced by compound K, a recently identified and potent positive allosteric modulator of P2X7. Based on our observations, we propose that high ATP concentrations induce early cell swelling, loss of mitochondrial membrane potential, plasma membrane rupture, and LDH release. ...
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 ...
Adenylyl cyclases and the interaction between calcium and cAMP signalling. Spanning binding sites on allosteric proteins with polymer-linked ligand dimers
BioAssay record AID 622165 submitted by ChEMBL: Positive allosteric modulation of AMPA receptor in Sprague-Dawley rat hippocampal neuron assessed as glutamate-induced response pre-treated for 20 secs by patch-clamp electrophysiology.
1) Allosteric regulation is the regulation of the activity of allosteric enzymes. (See also Allosteric binding sites; Allosteric enzymes).. ...
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 - Parallel synthesis of N-biaryl quinolone carboxylic acids as selective M1 positive allosteric modulators. AU - Yang, Feng V.. AU - Shipe, William D.. AU - Bunda, Jaime L.. AU - Nolt, M. Brad. AU - Wisnoski, David D.. AU - Zhao, Zhijian. AU - Barrow, James C.. AU - Ray, William J.. AU - Ma, Lei. AU - Wittmann, Marion. AU - Seager, Matthew A.. AU - Koeplinger, Kenneth A.. AU - Hartman, George D.. AU - Lindsley, Craig W.. PY - 2010/1/15. Y1 - 2010/1/15. N2 - An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M1 positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.. AB - An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M1 positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.. KW - M. KW - Positive allosteric ...
TY - JOUR. T1 - Dissecting a role of a charge and conformation of Tat2 peptide in allosteric regulation of 20S proteasome. AU - Witkowska, Julia. AU - Karpowicz, Przemysław. AU - Gaczynska, Maria. AU - Osmulski, Pawel A.. AU - Jankowska, Elzbieta. PY - 2014/8. Y1 - 2014/8. N2 - Proteasome is a proteolytic factory that constitutes an essential part of the ubiquitin-proteasome pathway. The involvement of proteasome in regulation of all major aspects of cellular physiology makes it an attractive drug target. So far, only inhibitors of the proteasome entered the clinic as anti-cancer drugs. However, proteasome regulators may also be useful for treatment of inflammatory and neurodegenerative diseases. We established in our previous studies that the peptide Tat2, comprising the basic domain of HIV-1 Tat protein: R49KKRRQRR56, supplemented with Q66DPI 69 fragment, inhibits the 20S proteasome in a noncompetitive manner. Mechanism of Tat2 likely involves allosteric regulation because it competes with ...
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.
The main objective when analyzing equilibrium data are to identify elements that respond to external forces, and to quantify their interactions with the catalytic unit, which in ion channels is the conducting pore. Quaternary descriptions of enzyme function have been useful in studying regulatory proteins-most notably hemoglobin, widely considered the poster child of protein allosteric theory. Modeling hemoglobin using sophisticated variants of the classical Monod-Wyman-Changeux (MWC) equation (Monod et al., 1965) has achieved impressive insight into its allosteric machinery (Eaton et al., 2007). A K+ channel whose regulation, at a basic level, is formulaically similar to that of hemoglobin (though mechanistically distinct), is the large-conductance voltage- and Ca2+-dependent (BK) channel. The BK channel derives its voltage dependence from four voltage-sensing (J) domains located within the membrane electric field, and also to a small degree from the pore (L) itself. Calcium sensors (K) are ...
Positive allosteric modulators of the ionotropic glutamate receptor-2 (GluA2) are promising compounds for the treatment of cognitive disorders, e.g. Alzheimers disease. These modulators bind within the dimer interface of the LBD (ligand-binding domain) and stabilize the agonist-bound conformation slowing receptor desensitization and/or deactivation. In the present study, we employ isothermal titration calorimetry to determine binding affinities and thermodynamic details of binding of modulators of GluA2. A mutant of the LBD of GluA2 (LBD-L483Y-N754S) that forms a stable dimer in solution was used. The potent GluA2 modulator BPAM-97 was used as a reference compound. Evidence that BPAM-97 binds in the same pocket as the well-known GluA2 modulator cyclothiazide was obtained from X-ray structures. The LBD-L483Y-N754S:BPAM-97 complex has a Kd of 5.6 μM (ΔH=−4.9 kcal/mol, −TΔS=−2.3 kcal/mol; where 1 kcal≈4.187 kJ). BPAM-97 was used in a displacement assay to determine a Kd of 0.46 mM ...
USE OF SELECTIVE GABA A ALPHA 5 NEGATIVE ALLOSTERIC MODULATORS FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM CONDITIONS - diagram, schematic, and image 17 ...
Oxysterols are a class of endogenous signaling molecules that can activate the Hedgehog pathway, which has critical roles in development, regeneration and cancer. However, it has been unclear how oxysterols influence Hedgehog signaling, including whe
A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs. ...
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 ...
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 ...
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 ...
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...
Drugs. 2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) from Ascent Scientific (Weston-SuperMare, UK). Dihydro-β-erythroidine hydrobromide (DHβE), methyllycaconitine (MLA), and PNU-120596 were purchased from Tocris Bioscience (Bristol, UK). SB-206553, picrotoxin, atropine, (-)nicotine, and acetylcholine were purchased from Sigma Chemical (Poole, Dorset, UK).. Recombinant and Native Cell Lines. GH4C1 cells stably transfected with pCEP4/rat α7 nAChR (α7-nAChR-GH4C1) were used in this study and maintained in poly-d-lysine-coated flasks in F10 medium supplemented with 15% horse serum and 2.5% fetal bovine serum, 1% penicillin-streptomycin, and 200 mg/ml hygromycin B at 37°C in a humidified 5% CO2 incubator. The 5-HT3A receptor cDNA was cloned from human brain RNA, and the rat α7 nAChR was cloned from PC12 cells. Human SHSY5Y cells and TE671 endogenously expressing α3- and α1-containing receptors, respectively, were used.. Measurement of Intracellular Ca2+Using the ...
in Journal of Chemical Information & Modeling (2014), 54(12), 3404-3416. Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimers disease. In the present study, we describe the ... [more ▼]. Positive allosteric modulation of the ionotropic glutamate receptor GluA2 presents a potential treatment of cognitive disorders, for example, Alzheimers disease. In the present study, we describe the synthesis, pharmacology, and thermodynamic studies of a series of monofluoro-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. Measurements of ligand binding by isothermal titration calorimetry (ITC) showed similar binding affinities for the modulator series at the GluA2 LBD but differences in the thermodynamic driving forces. Binding of 5c (7-F) and 6 (no-F) is enthalpy driven, and 5a (5-F) and 5b (6-F) are entropy driven. For 5d (8-F), both quantities were equal in size. Thermodynamic integration ...
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PRF readers can get free access to a selected Journal of Pain paper each month, thanks to the American Pain Society. Get the free full text of the selection from the December 2017 issue here.. ...
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 ...
cAMP (adenosine 3,5-cyclic monophosphate) is a ubiquitous second messenger that activates a multitude of essential cellular responses. Two key receptors for cAMP in eukaryotes are protein kinase A (PKA) and the exchange protein directly activated by cAMP (EPAC), which is a recently discovered guanine nucleotide exchange factor (GEF) for the small GTPases Rap1 and Rap2. Previous attempts to investigate the mechanism of allosteric activation of eukaryotic cAMP-binding domains (CBDs) at atomic or residue resolution have been hampered by the instability of the apo form, which requires the use of mixed apo/holo systems, that have provided only a partial picture of the CBD apo state and of the allosteric networks controlled by cAMP. Here, we show that, unlike other eukaryotic CBDs, both apo and cAMP-bound states of the EPAC1 CBD are stable under our experimental conditions, providing a unique opportunity to define at an unprecedented level of detail the allosteric interactions linking two critical ...
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:. ...
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 ...
4N7O: Capturing the haemoglobin allosteric transition in a single crystal form; Crystal structure of half-liganded human haemoglobin with phosphate at 2.5 A resolution.
Journal Article: Allosteric Activation of Bacterial Swi2/Snf2 (Switch/Sucrose Non-fermentable) Protein RapA by RNA Polymerase: BIOCHEMICAL AND STRUCTURAL STUDIES ...
Davis, B.C.; Brown, J.A.; Thorpe, I.F., 2016: Allosteric inhibitors have distinct effects, but also common modes of action, in the HCV polymerase
The Neddylation pathway was recently validated as a cancer target. The SENP8 protease processes the precursor of Nedd8 and is essential for its activation. Base...
Allosteric regulation provides highly specific ligand recognition and signaling by transmembrane protein receptors. Unlike functions of protein molecular machines that rely on large-scale conformational transitions, signal transduction in receptors appears to be mediated by more subtle structural motions that are difficult to identify. We describe a theoretical model for allosteric regulation in receptors that addresses a fundamental riddle of signaling: What are the structural origins of the receptor agonism (specific signaling response to ligand binding)? The model suggests that different signaling pathways in bovine rhodopsin or human beta(2)-adrenergic receptor can be mediated by specific structural motions in the receptors. We discuss implications for understanding the receptor agonism, particularly the recently observed "biased agonism" (selected activation of specific signaling pathways), and for developing rational structure-based drug-design strategies. ...
1.A.10 The Glutamate-gated Ion Channel (GIC) Family of Neurotransmitter Receptors. Members of the GIC family are homo or heterotetrameric complexes in which each of the 4 subunits is of 800-1000 amino acyl residues in length (Mayer, 2006) (see Simeone et al. 2004 for a review). They have a modular architecture with four domains: the intracellular C-terminal domain (CTD) that is involved in synaptic targeting, the transmembrane domain (TMD) that forms the ion channel, the membrane-proximal ligand-binding domain (LBD) that binds agonists such as L-glutamate, and the distal N-terminal domain (NTD). The extracellular portion, comprised of the LBD and NTD, is loosely arranged, mediating complex allosteric regulation (Krieger et al. 2015). The structures of these receptor-channels have been reviewed with emphasis on their function and pharmacology (Regan et al. 2015). A hydrophobic box in both AMPA and NMDA receptors plays a role in channel desensitization (Alsaloum et al. 2016). Activation and ...
Structure-function analyses reveal the mechanistic underpinnings of inside-out transmembrane signaling that controls periplasmic proteolysis, and thereby biofilm formation, in bacteria and may be relevant in the context of other signaling proteins with similar control elements.
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Metabolism controls gene expression through allosteric interactions between metabolites and transcription factors. These interactions are usually measured with in vitro assays, but there are no methods to identify them at a genome-scale in vivo. Here we show that dynamic transcriptome and metabolome data identify metabolites that control transcription factors in E. coli. By switching an E. coli culture between starvation and growth, we induce strong metabolite concentration changes and gene expression changes. Using Network Component Analysis we calculate the activities of 209 transcriptional regulators and correlate them with metabolites. This approach captures, for instance, the in vivo kinetics of CRP regulation by cyclic-AMP. By testing correlations between all pairs of transcription factors and metabolites, we predict putative effectors of 71 transcription factors, and validate five interactions in vitro. These results show that combining transcriptomics and metabolomics generates hypotheses about
Enzymes are extremely useful and effective in many biochemical reactions but only at the right time and place. Enzyme activity is regulated in five different ways:. Allosteric control:Allosteric enzymes contain distinct regulatory sites and multiple functional sites. The protein is significantly controlled when small signal molecules bind to these regulatory sites. Also allosteric enzymes show cooperativity, which means that activity at one functional site will affect the other functional site as well.. Multiple Forms of Enzymes: Isoenzymes or Isozymes are homologous enzymes in an organism that catalyze the same reaction but are a little bit different in their structure, Km and Vmax values, and regulatory properties. Isozymes allow a reaction to be regulated at distinct locations or times.. Reversible Covalent Modification: The catalytic properties of enzymes can be altered by a covalent binding of a modifying group, most commonly to a phosphoryl group. Usually ATP will serve as a donor for ...
Nörenberg W, Sobottka H, Hempel C, Plötz T, Fischer W, Schmalzing G, Schaefer M. Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors. Br J Pharmacol 167:48-66, 2012 ...
Hi, Can anyone please explain what is proteolysis. I looked it up and all I understand is that it is the hydrolysis of proteins which causes them to break down. Is this correct or not? If it is not please tell me what it is? Also please explain what is the Ka-Mg2+ . My understanding is that ka is the acid dissociation constant. But I thought that applied to acid which gain electron. But how does it apply to Mg2+. If I am totally wrong please explain what it may be. I am reading an article on Allosteric inhibition of Fructose-1,6-bisphosphate and it says that mutated ones have a higher Ka-Mg2+. what does that mean? Thanx ...
5) Cytochrome P450s represent an important class of monooxygenases, which play important roles in the hydroxylation of endogenous physiological substrates as well as a vast range of drugs and other compounds foreign to the organism (xenobiotics2 ). Exposure to such xenobiotics results in the induction of particular families of P450 proteint. , 1996). With the exception of microbial P450s, the majority of P450s are membrane bound, associated either with the inner membrane of the mitochondria or the endoplasmic reticulum (microsomal) membrane. This reflects the cooperativity of oxygen binding - the fourth oxygen molecule binds with 100-fold greater affinity than the first. It is known that, like other allosteric proteins, haemoglobin exists in two distinct and different conformations, corresponding to the T (deoxy) and R (oxy) states. Indeed, the conformations of oxy and deoxyhaemoglobins are so different, that crystals of deoxyhaemoglobin shatter when oxygen is introduced. But since the haem ...
Epitope Fluctuations in the Human Papillomavirus Are Under Dynamic Allosteric Control: A Computational Evaluation of a New Vaccine Design Strategy
4EIZ: Mechanistic analysis of allosteric and non-allosteric effects arising from nanobody binding to two epitopes of the dihyrofolate reductase of Escherichia coli.
Sigma-Aldrich offers abstracts and full-text articles by [Erwann Le Rouzic, Damien Bonnard, Sophie Chasset, Jean-Michel Bruneau, Francis Chevreuil, Frédéric Le Strat, Juliette Nguyen, Roxane Beauvoir, Céline Amadori, Julie Brias, Sophie Vomscheid, Sylvia Eiler, Nicolas Lévy, Olivier Delelis, Eric Deprez, Ali Saïb, Alessia Zamborlini, Stéphane Emiliani, Marc Ruff, Benoit Ledoussal, François Moreau, Richard Benarous].
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. ...
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 ...
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.
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 Huang, Zhimin; Zhu Liang; Cao Yan; Wu Geng; Liu Xinyi; Chen Yingyi; Wang Qi; Shi Ting; Zhao Yaxue; Wang ... leading to rapid growth on allosteric findings. Allosteric Database (ASD) provides a central resource for the display, search ... and efficient way for regulation of biological macromolecule function induced by the binding of a ligand at an allosteric site ... Currently, ASD contains allosteric proteins from more than 100 species and modulators in three categories (activators, ...
A common mechanism is allosteric regulation. This is when a substrate binds a repressor protein and causes it to undergo a ...
Allosteric regulation Haldane Effect Root effect Bohr; Hasselbalch, Krogh. "Concerning a Biologically Important Relationship - ... The Bohr effect hinges around allosteric interactions between the hemes of the haemoglobin tetramer, a mechanism first proposed ...
Giladi, Moshe; Khananshvili, Daniel (2013-01-01). "Molecular determinants of allosteric regulation in NCX proteins". Advances ... Allosteric activation of NCX involves the binding of cytosolic Ca2+ to regulatory domains CBD1 and CBD2. The generalized ... A large central loop is not required for transport function and plays a role in regulation. In the preferred 9 TMS model for ... DiPolo, Reinaldo; Beaugé, Luis (2006-01-01). "Sodium/calcium exchanger: influence of metabolic regulation on ion carrier ...
Mechanisms of Cooperativity and Allosteric Regulation in Proteins. Cambridge. Cambridge University PressISBN 0-521-38648-9 1992 ...
The concerted model (the Monod, Wyman and Changeux (MWC) model) of allosteric regulation requires all subunits to be in the ... Interconversion of morpheein forms can be a structural basis for allosteric regulation. A mutation that shifts the normal ... De Riel, Jon K.; Paulus, Henry (1978). "Subunit dissociation in the allosteric regulation of glycerol kinase from Escherichia ... De Riel, Jon K.; Paulus, Henry (1978). "Subunit dissociation in the allosteric regulation of glycerol kinase from Escherichia ...
... may use the morpheein model of allosteric regulation. Human genes that encode proteins with tryptase activity include ...
This protein may use the morpheein model of allosteric regulation. Lipoic acid GRCh38: Ensembl release 89: ENSG00000091140 - ... 2004). "Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by ...
This protein may use the morpheein model of allosteric regulation. Voet D; Voet JG. (2004). "The Personal Genome Project". ... This allows the independent regulation of the rates of methionine, lysine, and threonine production. The forms that produce ...
This protein may use the morpheein model of allosteric regulation. Glycerol Kinase (alternative name, ATP:glycerol 3- ...
This protein may use the morpheein model of allosteric regulation. Site-specific recombinase technology Masuda, Takao (2011-01- ...
Ahmad MF, Dealwis CG (2013). "The structural basis for the allosteric regulation of ribonucleotide reductase". Progress in ... Wyngaarden JB (1976). "Regulation of purine biosynthesis and turnover". Advances in Enzyme Regulation. 14: 25-42. doi:10.1016/ ... "Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization". Nature ... When a ligand binds a GPCR, an allosteric change in the G protein is triggered, causing GDP to leave and be replaced by GTP. ...
This protein may use the morpheein model of allosteric regulation. Human CBS performs a crucial step in the biosynthetic ... AdoMet is an allosteric activator that increases the Vmax of the CBS reaction but does not affect the Km for the substrates. In ... Allosteric activation of CBS by adoMet determines the metabolic fate of homocysteine. Mammalian CBS is activated 2.5-5-fold by ... The C-terminal domain of cystathionine β-synthase regulates its activity via both intrasteric and allosteric effects and is ...
This protein may use the morpheein model of allosteric regulation. Hu Y, Komoto J, Huang Y, et al. (June 1999). "Crystal ...
It is 10,000 times more toxic to HIV than it is to cells." This protein may use the morpheein model of allosteric regulation. ...
CTP is also subject to various forms of allosteric regulation. GTP acts as an allosteric activator that strongly promotes the ... The reaction product CTP also serves as an allosteric inhibitor. The triphosphate binding site overlaps with that of UTP, but ... Kassel KM, Au da R, Higgins MJ, Hines n M, Graves LM (2010). "Regulation of human cytidine triphosphate synthetase 2 by ... Endrizzi J, Kim H, Anderson PM, Baldwin EP (2005). "Mechanisms of product feedback regulation and drug resistance in cytidine ...
This protein may use the morpheein model of allosteric regulation. Ethanol is dehydrogenated to acetaldehyde by alcohol ... LDH undergoes transcriptional regulation by PGC-1α. PGC-1α regulates LDH by decreasing LDH A mRNA transcription and the ...
This protein may use the morpheein model of allosteric regulation. As of late 2007, two structures have been solved for this ...
This protein may use the morpheein model of allosteric regulation. GRCh38: Ensembl release 89: ENSG00000062485 - Ensembl, May ...
This protein may use the morpheein model of allosteric regulation. At the juncture of lipid synthesis and oxidation pathways, ... The regulation of mammalian ACC is complex, in order to control two distinct pools of malonyl CoA that direct either the ... An allosteric inhibitor of ACC has been granted fast-track status for the treatment of NASH (non-alcoholic steatohepatitis). ... Other allosteric activators include glutamate and other dicarboxylic acids. Long and short chain fatty acyl CoAs are negative ...
This protein may use the morpheein model of allosteric regulation. PFK is about 300 amino acids in length, and structural ... one involved in ATP binding and the other housing both the substrate-binding site and the allosteric site (a regulatory binding ...
This protein may use the morpheein model of allosteric regulation. Ribonuclease Raines RT (1998). "Ribonuclease A". Chem. Rev. ...
This protein may use the morpheein model of allosteric regulation. As its name indicates, glyceraldehyde 3-phosphate ... Campanella ME, Chu H, Low PS (February 2005). "Assembly and regulation of a glycolytic enzyme complex on the human erythrocyte ... However, researchers have reported different regulation of GAPDH under specific conditions. For example, the transcription ...
This protein may use the morpheein model of allosteric regulation. DAAO is used as a biocatalyst in several biotechnological ... mammalian D-amino acid oxidase has been connected to the brain D-serine metabolism and to the regulation of the glutamatergic ...
"Allosteric initiation and regulation of catalysis with a molecular knot". Science. 352 (6293): 1555-1559. Bibcode:2016Sci... ...
Karaoglu D, Kelleher DJ, Gilmore R (October 2001). "Allosteric regulation provides a molecular mechanism for preferential ...
... the crystal structures reveal conformational changes with implications for allosteric regulation. ... CONFORMATIONAL CHANGES AND IMPLICATIONS FOR ALLOSTERIC REGULATION. ...
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule ... B - Allosteric site. C - Substrate. D - Inhibitor. E - Enzyme. This is a diagram of allosteric regulation of an enzyme. ... Ensemble models of allosteric regulation enumerate an allosteric systems statistical ensemble as a function of its potential ... allosteric regulation is also expected to play an increasing role in drug discovery and bioengineering. The AlloSteric Database ...
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule ... B - Allosteric site. C - Substrate. D - Inhibitor. E - Enzyme. This is a diagram of allosteric regulation of an enzyme. ... Allosteric residues and their predictionEdit. Not all protein residues play equally important roles in allosteric regulation. ... Ensemble models of allosteric regulation enumerate an allosteric systems statistical ensemble as a function of its potential ...
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule ... Ensemble models of allosteric regulation enumerate an allosteric systems statistical ensemble as a function of its potential ... the allosteric site). The sequential model of allosteric regulation holds that subunits are not connected in such a way that a ... allosteric regulation is also expected to play an increasing role in drug discovery and bioengineering. The AlloSteric Database ...
Prepaying the entropic cost for allosteric regulation in KIX. Sean M. Law, Jessica K. Gagnon, Anna K. Mapp and Charles L. ... Our results capture an increase in affinity for the peptide in the allosteric site when KIX is prebound by a complementary ... Here, we investigate the allosteric mechanism involving a promiscuous protein that serves as a hub for a variety of ... It is presumable that the features identified in this allosteric mechanism are conserved between the central protein and other ...
Allosteric regulation of phosphofructokinase controls the emergence of glycolytic oscillations in isolated yeast cells. Journal ... The oscillatory manifold could be approximated by allosteric control values of phosphofructokinase for ATP and AMP. ...
Engineering allosteric regulation in protein kinases. By David Pincus, Jai P. Pandey, Zoë A. Feder, Pau Creixell, Orna Resnekov ... Engineering allosteric regulation in protein kinases. By David Pincus, Jai P. Pandey, Zoë A. Feder, Pau Creixell, Orna Resnekov ... Engineering allosteric regulation in protein kinases Message Subject. (Your Name) has forwarded a page to you from Science ...
... emphasizing that both enzymatic function and allosteric regulation require a coupling between ligand binding and protein ... Finally, sites with high binding leverage but no known biological function could be latent allosteric sites, and thus drug ... We show that high binding leverage is a characteristic of both allosteric sites and catalytic sites, ... Author Summary Allosteric protein regulation is the mechanism by which binding of a molecule to one site in a protein affects ...
Postdoctoral Position - Allosteric Regulation in the KDM5 Family of Histone Demethylases. Submitted by mariabaias on Thu, 2015- ... Postdoctoral Position - Allosteric Regulation in the KDM5 Family of Histone Demethylases. *Postdoctoral Position Available in ... Postdoctoral Position - Allosteric Regulation in the KDM5 Family of Histone Demethylases. *Postdoctoral Position Available in ... The goal of this work is to expand our understanding of the mechanisms that underlie regulation of chromatin methylation and ...
Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling.. Wang J1 ... Due to the allosteric coupling of channel opening and ligand binding, changes in cellular electrical activity that alter the ... These changes in ligand binding produce long-lasting changes in channel function which can contribute to the regulation of ...
Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. By Basil P. Hubbard, Ana P. Gomes, Han Dai, Jun ... Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. By Basil P. Hubbard, Ana P. Gomes, Han Dai, Jun ... Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators Message Subject. (Your Name) has forwarded a page ... Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs. ...
Targeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer. Jamin D. Steffen, Renee M. Tholey, Marie- ... Targeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer. Jamin D. Steffen, Renee M. Tholey, Marie- ... Targeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer. Jamin D. Steffen, Renee M. Tholey, Marie- ... Targeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer Message Subject (Your Name) has forwarded a ...
Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges.. ... Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges ... Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges ... Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges ...
Measure your knowledge about allosteric regulation of enzymes. Test your knowledge about this subject with quiz questions on ... Connect regulated enzymes to forms of allosteric regulation Skills Practiced. This worksheet and quiz let you practice the ... Reading comprehension - ensure that you draw the most important information from the related lesson on allosteric regulation of ... This quiz and worksheet will assess your understanding of allosteric regulation of enzymes. You will need to understand ...
Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek- ... Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek- ... which forms the allosteric pocket (Fig. 2 B-E). The side chain of Phe322 is found at the bottom of the allosteric pocket. The ... Similar to BPTES, compounds 2-4 all resides within the hydrophobic cluster of the allosteric pocket (Fig. S3 C-F).The side ...
Allosteric regulation is an efficient mechanism for modulation and regulation of protein activity to prevent non‐specific ... Allosteric regulation of rhomboid intramembrane proteolysis. Elena Arutyunova, Pankaj Panwar, Pauline M Skiba, Nicola Gale, ... Traut TW (1994) Dissociation of enzyme oligomers: a mechanism for allosteric regulation. Crit Rev Biochem Mol Biol 29: 125-163 ... The regulation of substrate binding and enzymatic activity for many serine proteases is achieved by allosteric interactions. ...
Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation ... Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation ... Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation ... Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation ...
This study is the first to observe that the use of Cl− as an allosteric inhibitor causes appreciable changes in the catalytic ... It is clear that the discovery of new allosteric sites of the C56 family of peptidases may generate opportunities for ... obtained from this study are expected to stimulate further biochemical studies on the structures and mechanisms of allosteric ... Keywords: oligomeric protease; allosteric regulation; molecular dynamics simulation oligomeric protease; allosteric regulation ...
Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting ... Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting ... Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting ... Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting ...
Inter-Enzyme Allosteric Regulation of Chorismate Mutase in Corynebacterium glutamicum: Structural Basis of Feedback Activation ... Structural details from the allosteric binding sites reveal that DAHP synthase is recruited as the dominant regulatory platform ...
Allosteric regulation of the partitioning of glucose-1-phosphate between glycogen and trehalose biosynthesis in Mycobacterium ... Allosteric regulation of the partitioning of glucose-1-phosphate between glycogen and trehalose biosynthesis in Mycobacterium ... None of the other two enzymes tested exhibited allosteric regulation. Conclusions: Results give information about how the ... The substrate specificity, kinetic parameters and allosteric regulation of each enzyme were determined. ADP-glucose ...
Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. Basil P. Hubbard, et al.. Science, March 8, 2013 ...
Structural and functional characterization of an unanticipated mode of allosteric activity regulation in ribonucleotide ... This type of allosteric regulation has been shown to provide an evolutionarily dynamic process by which allosteric regulation ... Allosteric regulation of an enzyme is defined as regulation of activity by binding of an effector molecule to a different ... Allosteric regulation of RNRs affects both substrate specificity and overall activity. The specificity regulation has been ...
Allosteric activity sites are shown with ATP modeled in cyan and dATP in red spheres. (E) Allosteric specificity regulation is ... First, allosteric activity regulation modulates the overall size of dNTP pools. ATP or dATP binding at an allosteric activity ... The second form of allosteric regulation is specificity regulation, which maintains the proper relative ratios of dNTPs in the ... Allosteric activity regulation is achieved by interconversion between an active α2β2 complex in the presence of the allosteric ...
committed step in a pathway Allosteric regulation (mechanism) Binding of ATP to a non-substrate (allosteric) site on the enzyme ... committed step in a pathway Allosteric regulation (mechanism) Binding of ATP to a non-substrate (allosteric) site on the enzyme ... Regulation of Glycolysis Learning Objectives: List the points of regulation in glyco ... Net reaction rate is: Inhibited by ↑ATP Accelerated by ↑ADP Feedback regulation (principle) End products of biochemical ...
  • The goal of this work is to expand our understanding of the mechanisms that underlie regulation of chromatin methylation and consequently transcription. (weizmann.ac.il)
  • The new structural insights obtained from this study are expected to stimulate further biochemical studies on the structures and mechanisms of allosteric proteases. (mdpi.com)
  • Uhlin and Eklund, 1994 ), and the β 2 subunit utilizes a largely helical secondary structure to house the radical cofactor ( Sjöberg and Reichard, 1977 ) ( Figure 1B-C ). As a central controller of nucleotide metabolism, RNR uses multiple allosteric mechanisms to maintain the balanced deoxyribonucleoside triphosphate (dNTP) pools that are required for accurate DNA replication. (elifesciences.org)
  • he will know the processes of production and use of energy in the cell and the role played by the mitochondria as well as the mechanisms of regulation of the main enzymatic reactions in relation to the cellular metabolism. (unige.it)
  • Mechanisms of enzymatic regulation. (unige.it)
  • The well-defined character of the AMPK drug site, and its regulation through reversible phosphorylation, has led to speculation that synthetic activators (991, A-769662) and salicylate are mimicking an endogenous metabolite(s) that would be capable of sustaining AMPK signaling in the absence of pThr172 1 , 17 . (nature.com)
  • Oxysterols are allosteric activators of the oncoprotein Smoothened. (biomedsearch.com)
  • In comparison, function and regulation of LGA is not well studied, although it was recently shown to be linked to p53 pathway ( 13 , 14 ). (pnas.org)
  • Structural details from the allosteric binding sites reveal that DAHP synthase is recruited as the dominant regulatory platform to control the shikimate pathway, similar to the corresponding enzyme complex from Mycobacterium tuberculosis. (uio.no)
  • L0710ap - committed step in a pathway Allosteric. (coursehero.com)
  • In chapter 4 a potential intramolecular communication pathway from the allosteric to the active site is probed by the generation of several single site mutations. (canterbury.ac.nz)
  • It does use some Fructose-6-P from the pathway, but Fructose-2,6-bisP is strictly an allosteric regulator of PFK-1. (csudh.edu)
  • Rabbit muscle pyruvate kinase (RMPK) is an important allosteric enzyme of the glycolytic pathway catalyzing a transfer of the phosphate from phosphoenolpyruvate (PEP) to ADP. (utmb.edu)
  • In eukaryotic algae (except dinoflagellates) and oceanic cyanobacteria the first step in sulphate assimilation, catalysed by ATP sulfurylase (ATPS) is subject to redox regulation, whereas in vascular plants APS reductase is the main control point in the pathway. (springer.com)
  • Although there is a long history to engineer light-activatable proteins, for example ion channels and kinases, the development of light-induced allosteric modulations of pharmacological importance - is a more recent phenomenon. (riken.jp)
  • The artificial regulation of proteins by light is an emerging subdiscipline of synthetic biology. (uni-regensburg.de)
  • Stern-Volmer quenching of active site-labeled fluorophore suggested that the allosteric regulators induce intermediate structural changes in the active site as compared to those that display ~80-100% efficacy. (sdsc.edu)
  • To elucidate the structural determinants of PDE6 allosteric regulators, we biochemically characterized PDE6 complexes in various allosteric states (Pαβ, Pαβ-cGMP, Pαβγ2, and Pαβγ2-cGMP) with a quantitative cross-linking/mass spectrometry approach. (unh.edu)
  • In particular, based upon the published results of structural and biochemical analysis of CSK and CHK, we attempt to chart the allosteric networks in CSK and CHK that govern their catalysis and ability to inhibit SFKs. (sahmriresearch.org)
  • Allosteric regulation of type I hexokinase: A site-directed mutational study indicating location of the functional glucose 6-phosphate binding site in the N-terminal half of the enzyme. (duke.edu)
  • The CjeATP-PRT Core characteristics suggest that it exists in a permanently inhibited conformation, highlighting the requirement of the regulatory domain not only for feedback regulation but also for enzyme function. (canterbury.ac.nz)
  • Thus, our hypothesis is that the disulfide bonds in R2-Ig regulate anthrax toxin action through allosteric effects on the conformation of R2-VWA, hence interfering with PA prepore-to-pore conversion and/or membrane insertion. (grantome.com)
  • By engineering conformationally locked DNMT3A variants as novel tools to study the allosteric regulation of this enzyme, we show that MeCP2 stabilizes the closed, autoinhibitory conformation of DNMT3A. (mpg.de)
  • Characterizations of light-induced allosteric modulations in the presence of inhibitors (Zn2+ and ifenprodil) and potentiators (spermine) have provided a unified view of how the same N-terminal domains of both subtypes, distant to the agonists binding domains, bidirectionally modulate receptors functions. (riken.jp)
  • Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges. (nih.gov)
  • Non-hub kinless nodes (R4) are located in turn on the interface between chains and play a key role in the concerted motion underlying the allosteric regulation of hemoglobin. (thefreedictionary.com)
  • Direct allosteric regulation between the GAF domain and catalytic domain of photoreceptor phosphodiesterase PDE6. (unh.edu)
  • Allosteric communication between GAF and catalytic domains is reciprocal, in that drug binding to the catalytic domain slowed cGMP dissociation from the GAF domain. (unh.edu)
  • It is clear that the discovery of new allosteric sites of the C56 family of peptidases may generate opportunities for pharmaceutical development and increases our understanding of the basic biological processes of this peptidase family. (mdpi.com)
  • It is well known that (but not understood how) residues far away from Hsp90's nucleotide binding pocket can regulate its ATPase activity, a phenomenon called allosteric regulation. (elsevier.com)
  • Antibody binding rendered β-sheet A - on the opposite face of the molecule - more liable to adopt an 'open' state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of pre-formed serpin-enzyme complex following mAb 4B12 binding. (biochemj.org)
  • We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage-dependent catalytic activation. (aacrjournals.org)