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)

*Pyruvate kinase

Allosteric regulation is the binding of an effector to a site on the protein other than the active site, causing a ... "The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate". Structure. 6 (2): 195-210. doi:10.1016/S0969-2126( ... "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 ...

*Glutamate dehydrogenase

Allosteric regulation: This protein may use the morpheein model of allosteric regulation. Allosteric inhibitors: Guanosine ... Mutations alter the allosteric binding site of GTP cause permanent activation of glutamate dehydrogenase lead to disorder known ... This regulation is relaxed in response to caloric restriction and low blood glucose. Under these circumstances, glutamate ... Monod J, Wyman J, Changeux JP (1965). "On the Nature of Allosteric Transitions: A Plausible Model". J Mol Biol. 12: 88-118. doi ...

*Allosteric regulation

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 system's 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 ...

*ASD (database)

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, ...

*Derepression

A common mechanism is allosteric regulation. This is when a substrate binds a repressor protein and causes it to undergo a ...

*Bohr effect

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 ...

*Calcium:cation antiporter

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 ...

*Max Perutz

Mechanisms of Cooperativity and Allosteric Regulation in Proteins. Cambridge. Cambridge University PressISBN 0-521-38648-9 1992 ...

*Morpheein

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 ...

*Tryptase

... may use the morpheein model of allosteric regulation. Human genes that encode proteins with tryptase activity include ...

*Dihydrolipoamide dehydrogenase

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 ...

*Aspartate kinase

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 ...

*Glycerol kinase

This protein may use the morpheein model of allosteric regulation. Glycerol Kinase (alternative name, ATP:glycerol 3- ...

*Integrase

This protein may use the morpheein model of allosteric regulation. Site-specific recombinase technology Masuda, Takao (2011-01- ...

*Nucleoside triphosphate

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. ...

*Cystathionine beta synthase

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 ...

*S-adenosyl-L-homocysteine hydrolase

This protein may use the morpheein model of allosteric regulation. Hu Y, Komoto J, Huang Y, et al. (June 1999). "Crystal ...

*Cyanovirin-N

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 synthetase

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 ...

*Lactate dehydrogenase

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 ...

*Farnesyltranstransferase

This protein may use the morpheein model of allosteric regulation. As of late 2007, two structures have been solved for this ...

*Citrate synthase

This protein may use the morpheein model of allosteric regulation. GRCh38: Ensembl release 89: ENSG00000062485 - Ensembl, May ...

*Acetyl-CoA carboxylase

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 ...

*Phosphofructokinase

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 ...

*Bovine pancreatic ribonuclease

This protein may use the morpheein model of allosteric regulation. Ribonuclease Raines RT (1998). "Ribonuclease A". Chem. Rev. ...

*Metabolism

This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway. Extrinsic ... There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to ... Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. ... Brand M (1997). "Regulation analysis of energy metabolism". J Exp Biol. 200 (Pt 2): 193-202. PMID 9050227. Soyer O, Salathé M, ...

*Glyceraldehyde 3-phosphate dehydrogenase

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 ...
Fig. 2. Effect of compounds on D2-mediated [35S]-GTPγS binding. The results are mean and S.E.M. from triplicate determinations in a single representative experiment that was repeated twice. (A) The R isomer lacks direct effects. The response was basal in the absence of dopamine (DA). (B) The R isomer caused a greater potentiation of D2 receptor signaling in the presence of a low concentration of dopamine than the racemate in a concentration-related manner. The S isomer lacked effects. Results are normalized to fitted max DA response and minimum (basal) response in presence of EC20 [DA]. (C) In the presence of 10 μM of the R isomer, the potency and efficacy of dopamine was increased compared with dopamine alone. The presence of the S isomer (10 μM) had no effect. (D) In the presence of 10 μM of the R isomer, the potency and efficacy of quinpirole was increased compared with quinpirole alone. ...
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 ...
Author Summary A common means of biological regulation is allostery, in which an effector molecule binds to one site on a protein and induces a conformational change which changes activity at a distant active site. Frequently high resolution structures are determined for one state of an allosteric protein but not the other. To probe the allosteric conformational changes in such cases, we describe a computational method for predicting the structure of one allosteric state of a protein starting with knowledge of another. Our method also provides a detailed map of the free energy landscape traversed in an allosteric transition and reveals the coupling between interacting residue pairs that underlies the transition.
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.
BioAssay record AID 581576 submitted by ChEMBL: Displacement of [3H]3-methoxy-PEPy from rat mGluR5 receptor allosteric binding site at 30 uM.
1) Allosteric regulation is the regulation of the activity of allosteric enzymes. (See also Allosteric binding sites; Allosteric enzymes).. ...
Allosteric ligands of G protein-coupled receptors (GPCRs) bind to sites that are topographically distinct from the orthosteric site. AC-42 and 77-LH-28-1 are functionally selective M1 muscarinic acetylcholine (mACh) receptor allosteric agonists that are able to activate the M1 mACh receptor in the absence of an orthosteric ligand. In the present study, a variety of signalling pathways activated by AC-42 and 77-LH-28-1 have been investigated and compared with those activated by orthosteric agonists in Chinese hamster ovary (CHO) cells recombinantly expressing human M1 mACh receptors. Both orthosteric and allosteric agonists are able to activate Gαq/11-dependent signalling as demonstrated by concentration-dependent increases in [35S]-GTPγS binding to Gαq/11 subunits, [³H]-inositol phosphate accumulation and Ca²+ mobilisation. Both AC-42 and 77-LH-28-1 are also able to activate extracellular signal-regulated kinase 1/2 and cyclic AMP response-element binding protein (CREB). However, while all ...
Glycine receptors (GlyRs) are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs) have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA) are positive modulators of α(1), α(2) and α(3) GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly) potentiate α(1) GlyRs but inhibit α(2) and α(3). This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM) region 2 and intracellular lysine 385 determine ...
The main objective when analyzing equilibrium data are to identify elements that respond to external forces, and to quantify their interactions with the catalytic unit, which in ion channels is the conducting pore. Quaternary descriptions of enzyme function have been useful in studying regulatory proteins-most notably hemoglobin, widely considered the poster child of protein allosteric theory. Modeling hemoglobin using sophisticated variants of the classical Monod-Wyman-Changeux (MWC) equation (Monod et al., 1965) has achieved impressive insight into its allosteric machinery (Eaton et al., 2007). A K+ channel whose regulation, at a basic level, is formulaically similar to that of hemoglobin (though mechanistically distinct), is the large-conductance voltage- and Ca2+-dependent (BK) channel. The BK channel derives its voltage dependence from four voltage-sensing (J) domains located within the membrane electric field, and also to a small degree from the pore (L) itself. Calcium sensors (K) are ...
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
Pyruvate kinase isoform M2 (PKM2) activity is subject to complex allosteric regulation. Recently, serine and SAICAR (succinylaminoimidazolecarboxamide ribose-5′-phosphate) were identified as previously unrecognized activators of PKM2. These findings add additional complexity to how PKM2 is regulated in cells and support the notion that modulating PKM2 activity enables cells to adapt their metabolic state to specific physiological contexts.. ...
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 ...
GABAA receptor (GABAAR) positive allosteric modulators that selectively modulate GABAARs containing β2- and/or β3- over β1-subunits have been reported across diverse chemotypes. Broadly, β2/3-selective GABAAR positive allosteric modulators are non-benzodiazepines (non-BZs), do not show α-subunit subtype selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here we report on a enantiomeric pair of non-BZ GABAAR positive allosteric modulators that demonstrate differential β-subunit subtype selectivity. We have tested this enantiomeric pair along with a series of other β2/3-subunit selective, α-subunit subtype selective, BZ and non-BZ GABAA positive allosteric modulators using electrophysiological, pharmacokinetic and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at β1-subunit containing GABAARs. Our findings provide an alternative strategy for designing anxioselective allosteric ...
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 ...
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 ...
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 ...
The neurotransmitter glutamate and its receptors have long been of interest to scientists involved in pharmaceutical research since dysfunction of the glutamatergic signalling pathway has been associated with the pathophysiology of several psychiatric and neurological disorders. The research on AMPAR positive allosteric modulators offers opportunities to modulate fast excitatory synaptic transmission and identify new potential therapeutic agents for a range of neurodiseases. The field of AMPAR modulators continues to be a dynamic area of drug discovery with a pronounced diversification of the chemotypes explored in recent years. This article reviews literature published in this area in the last 6 years, focusing on the new core templates, some derived from high-throughput screens, with an emphasis on structure-activity relationships, drug metabolism and pharmacokinetics properties, and pharmacological profiles of these series.. ...
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.. ...
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.
Regulation of Metabolism. How does the body know when to increase metabolism? Slow metabolism? What might be some indicators of energy status within the cell?. Requires communication. Works through allosteric regulation of enzyme activity. Mechanisms of Cellular Communication. Slideshow 6660494 by irene-dalton
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. ...
Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K. Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Molecular Pharmacology. 2001 Nov;60(5):963-71. PMID 11641424 ...
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 ...
Maxi-K channel gating is modulated by both membrane voltage and cytoplasmic Ca2+. Recent work has led to a quantitative understanding of this dual regulatory mechanism, derived from classical allosteric principles, in terms of the energetic coupling among membrane voltage, Ca2+ binding, and opening of the channels gate. Our new understanding of the gating pathway can be applied to the interpretation of mutagenesis experiments and may serve as an example in the analysis of other dually regulated signaling molecules.. ...
1FPE: Structural aspects of the allosteric inhibition of fructose-1,6-bisphosphatase by AMP: the binding of both the substrate analogue 2,5-anhydro-D-glucitol 1,6-bisphosphate and catalytic metal ions monitored by X-ray crystallography.
Hello Bio announced today the launch of JF-NP-26 (Caged-Raseglurant) - the first photoactive mGlu5 negative allosteric modulator (NAM) that allows optical control of analgesia in vivo.
There are 6 different types of ligands that bind the CB1 receptor. What is the difference between an inverse agonist and a negative allosteric modulator?
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].
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.
Sites of regulation. Feedback inhibition. Mechanism of allosteric inhibition. Repression and Induction. Mechanism of repression- Negative control. Mechanism of repression- control by co-repressor. Operon= a cluster of genes under control of a single promoter Regulon?. Arginine synthesis. Slideshow 4230737 by toni
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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One of the basic properties of protein|proteins is the ability to bind things ... things such as DNA, drugs, other proteins, cell surfaces, etc ... The ...
Taiho Pharmaceutical is developing TAS 117, a potent and selective oral allosteric non-ATP-competitive AKT inhibitor, for the treatment of solid tumours. Phase
View Notes - L0710ap from BIOS 20182 at UChicago. committed step in a pathway Allosteric regulation (mechanism) Binding of ATP to a non-substrate (allosteric) site on the enzyme causes a
Looking for online definition of allosteric enzymes in the Medical Dictionary? allosteric enzymes explanation free. What is allosteric enzymes? Meaning of allosteric enzymes medical term. What does allosteric enzymes mean?
General anesthetics bind reversibly to ion channels, modifying their global conformational distributions, but the underlying atomic mechanisms are not completely known. We examine this issue by way of the model protein Gloeobacter violaceous ligand-gated ion channel (GLIC) using computational molecular dynamics, with a coarse-grained model to enhance sampling. We find that in flooding simulations, both propofol and a generic particle localize to the crystallographic transmembrane anesthetic binding region, and that propofol also localizes to an extracellular region shared with the crystallographic ketamine binding site. Subsequent simulations to probe these binding modes in greater detail demonstrate that ligand binding induces structural asymmetry in GLIC. Consequently, we employ residue interaction correlation analysis to describe the internal allosteric network underlying the coupling of ligand and distant effector sites necessary for conformational change. Overall, the results suggest that the same
Barbiturates have special uses and are organized into 4 classes: ultrashort-, short-, intermediate- and long-acting. Empirically SARs of barbiturants are based on thousands of (animal) tested compounds.They have shown that R and R´ may not be H in position 5 (see figure 8). Also, position 5 confer sedative-hypnotic properties.[10] Generally alkyl branching in position 5 means less lipid solubility and less activity. Unsaturation show less activity in position 5 and alicyclic and aromatic rings show less potency. Polar substiuents (-NH2, -OH, -COOH) will decrease lipid solubility but it will also eliminate activity. R´´ in position 1 is usually, H but CH3 in that position yields less lipid solubility and duration. Exchanging S for O atom in position 2 produces thiobarbiturates, which are more lipid-soluble than the oxybarbiturates. In general, the more lipid-soluble the barbiturate, the more rapid its onset, the shorter its duration and the greater the degree of hypnotic activity. Barbiturates ...
TY - JOUR. T1 - Design of allosteric hammerhead ribozymes activated by ligand-induced structure stabilization. AU - Soukup, Garrett. AU - Breaker, Ronald R.. PY - 1999/7/15. Y1 - 1999/7/15. N2 - Background: Ribozymes can function as allosteric enzymes that undergo a conformational change upon ligand binding to a site other than the active site. Although allosteric ribozymes are not known to exist in nature, nucleic acids appear to be well suited to display such advanced forms of kinetic control. Current research explores the mechanisms of allosteric ribozymes as well as the strategies and methods that can be used to create new controllable enzymes. Results: In this study, we exploit the modular nature of certain functional RNAs to engineer allosteric ribozymes that are activated by flavin mononucleotide (FMN) or theophylline. By joining an FMN- or theophylline-binding domain to a hammerhead ribozyme by different stem II elements, we have identified a minimal connective bridge comprised of a G·U ...
Thrombin demonstrates a high level of allosteric regulation.[2] Allosterism in thrombin is regulated by the exosites 1 and 2 and the sodium binding site. A recent patent review has shown that the general consensus among researchers is that allosteric inhibitors may provide a more regulatable anticoagulant.[3] Some of the allosteric inhibitors discovered include DNA aptamers,[3] benzofuran dimers,[4] benzofuran trimers,[5] as well as polymeric lignins.[6] A new sulfated β-O4 lignin (SbO4L) has been discovered which has shown a dual mechanism of action for anti-thrombosis. This SbO4L shows allosteric inhibition of thrombin for fibrinogen, while providing a competitive inhibition of thrombin interaction with platelet glycoprotein Ibα (GPIbα), thereby preventing thrombin mediated platelet aggregation.[7] However, despite the growing interest and the advances in allosterism, no allosteric thrombin inhibitor has yet reached the stage of clinical trials.. ...
Valentini G., Chiarelli L., Fortin R., Speranza M.L., Galizzi A., Mattevi A.. Pyruvate kinase (PK) is critical for the regulation of the glycolytic pathway. The regulatory properties of Escherichia coli were investigated by mutating six charged residues involved in interdomain salt bridges (Arg(271), Arg(292), Asp(297), and Lys(413)) and in the binding of the allosteric activator (Lys(382) and Arg(431)). Arg(271) and Lys(413) are located at the interface between A and C domains within one subunit. The R271L and K413Q mutant enzymes exhibit altered kinetic properties. In K413Q, there is partial enzyme activation, whereas R271L is characterized by a bias toward the T-state in the allosteric equilibrium. In the T-state, Arg(292) and Asp(297) form an intersubunit salt bridge. The mutants R292D and D297R are totally inactive. The crystal structure of R292D reveals that the mutant enzyme retains the T-state quaternary structure. However, the mutation induces a reorganization of the interface with the ...
Our lab is interested in the biology and therapeutic potential of targeting Class C G protein-coupled receptors (GPCRs). We are predominantly focussed on two class members: metabotropic glutamate receptor subtype 5 (mGlu5) and the calcium-sensing receptor (CaSR). mGlu5 is an exciting new target for schizophrenia, Alzheimers disease, autism spectrum disorders and depression, whereas modulators of the CaSR are already in the clinic for hyperparathyroidism and are putative therapeutics for osteoporosis, calcium handling disorders, asthma and idiopathic pulmonary arterial hypertension. We are pursuing a novel class of therapeutics, called allosteric modulators, to selectively target these receptors. To facilitate rational drug design and discovery efforts, a better understanding of the functional consequences and structural basis of allosteric modulation is needed.. Available projects examine ...
The alpha (2)beta (2) tryptophan synthase complex is a model enzyme for understanding allosteric regulation. We report the functional and regulatory properties of the beta S178P mutant. Ser-178 is located at the end of helix 6 of the beta subunit, belonging to the domain involved in intersubunit signaling. The carbonyl group of beta Ser-178 is hydrogen bonded to Gly-181 of loop 6 of the alpha subunit only when alpha subunit ligands are bound. An analysis by molecular modeling of the structural effects caused by the beta S178P mutation suggests that the hydrogen bond involving alpha Gly-181 is disrupted as a result of localized structural perturbations. The ratio of alpha to beta subunit concentrations was calculated to be 0.7, as for the wild type, indicating the maintenance of a tight alpha-beta complex. Both the activity of the alpha subunit and the inhibitory effect of the alpha subunit ligands indole-3-acetylglycine and D,L-alpha -glycerol-3-phosphate were found to be the same for the mutant ...
Our laboratory has previously reported that bronchial epithelial cells (BEC) express a regulatory cascade of classic neurotransmitters and receptors that communicate in an almost neuronal-like manner to achieve physiologic regulation. In this paper we show that the similarity between neurotransmitter signaling in neurons and BEC extends to the level of transmitter receptor allosteric modulators. Lynx1 is a member of the ly-6/three finger superfamily of proteins, many of which modulate receptor signaling activity. Lynx1 specifically has been shown to modulate nicotinic acetylcholine receptor (nAChR) function in neurons by altering receptor sensitivity and desensitization. We now report that lynx1 forms a complex with α7 nAChR in BEC and serves to negatively regulate α7 downstream signaling events. Treatment of primary cultures of BEC with nicotine increased levels of nAChR subunits and that increase was potentiated by lynx1 knockdown. Lynx1 knockdown also potentiated the nicotine-induced ...
Chemical biology ; Sirtuin ; Sirtuin inhibitor ; Tenovins ; Allosteric ; RmlA ; QP601.5P5 ; Enzyme inhibitors ; Sirtuins ; Sirtuins--Inhibitors ; Allosteric regulation ; Nuclear magnetic resonance
A combined systematic alanine scanning and molecular modelling approach reveals the molecular basis for an allosteric inhibition mechanism of K+-flux gating in K2P channels.
Extensions of the allosteric model for hemoglobin », Nature, n° 230, 1971, pp. 224-227.. « Cooperative interactions of hemoglobin », Annu. Rev. Biochem., n° 44, 1975, pp. 209-232.. S. Edelstein, G. Dykes & R. H. Crepeau, « Three-dimensional reconstruction of the fibres of sickle cell haemoglobin », Nature, n° 272, 1978, pp. 506-510.. « Molecular topology in crystals and fibers of hemoglobin », S. J. Mol. Biol., n° 150, 1981, pp. 557-575.. S. Edelstein, D. W. Rodgers & R. H. Crepeau, « Pairings and polarities of the 14 strands in sickle cell hemoglobin fibers », Proc. Natl. Acad. Sci. USA, n° 84, 1987, pp. 6157-6161.. S. Edelstein, I. Irminger-Finger, E. Hurt, A. Roebuck & M. A. Collart, « MHP1, an essential gene in Saccharomyces cerevisiae required for microtubule function », J. Cell Biol., n° 135, 1996, pp. 1323-1339.. S. Edelstein & J.-P. Changeux, « Allosteric receptors after 30 years », Neuron, n° 21, 1998, pp. 959-980.. S. Edelstein & J.-P. Changeux, « Allosteric ...
It is rare that an unpublished piece of research or theory remains significant after half a century. It is also a wonderful example of the boundless curiosity of the late Francis Crick. A previously unpublished work by Francis Crick and Jeffries Wyman from 1965 is now available, together with Jean-Pierre Changeuxs recollections on the origins of the theory of Allostery and several important texts by various authors on the subject. These are part of a special issue of the Journal of Molecular Biology (JMB) published at the occasion of a Pasteur/EMBO Conference on Allosteric Interactions in Cell Signaling and Regulation to be held at the Pasteur Institute in Paris, May 14-17, 2013, to mark a half-century of research on this subject.. Early in 1963 an influential theory was published by Jacques Monod, Jean-Pierre Changeux and François Jacob in JMB to explain how binding of a regulatory molecule could influence the binding of a completely different kind of molecule at topographically distinct ...
Gabather has completed in vitro and in vivo experiments on the substances GT-001 - GT-006. The substances were tested in models for psychosis and anxiety, with very promising general results such as none of the substances having sedative side effects. The main focus has been on GT-002, which is generating promising results as a potential antipsychotic. In 2015 Gabather signed a research agreement with UNSW (University of New South Wales, Australia), and one of the resulting studies show that GT-002 acts as a positive allosteric modulator on the GabaA receptor. The difference from other positive allosteric modulators is that GT-002 does not affect the neuron population, which minimizes the risk of sedative or convulsive side effects. Further in-vitro studies show that GT-002 is also a highly selective substance. ...
Possible location the allosteric binding pocket of L. pneumophila dehydratase. The catalytic domain is highlightedin orange, whereasthe β domain is displayed i
On the basis of its MEK inhibitory activity, E6201 was shown here to be an ATP-competitive MEK inhibitor that is effective against BRAF-V600E melanoma in a preclinical setting. Furthermore, we showed that E6201 is effective in a preclinical model against BRAF-V600E melanoma harboring the MEK1-C121S mutation. Almost all of the MEK inhibitors previously reported are allosteric inhibitors, not ATP-competitive inhibitors (37). Our docking simulation showed that E6201 and selumetinib bind to different sites when they dock with MEK. These results suggest that the inhibitory mode of action of E6201 is different from that of allosteric MEK inhibitors and that E6201 merits further investigation in a clinical setting against both MEK-WT melanomas and melanomas harboring MEK with mutations at the allosteric site.. The MEK1-C121S mutation, which confers resistance to vemurafenib, increases MEK activity independently from BRAF and also confers resistance to the allosteric MEK inhibitor selumetinib (12). Our ...
Significant advances have been made over recent years in our understanding of the tremendous complexity underlying the function of the human brain, in particular gaining insight into the mechanisms of synaptic plasticity which are key to developmental, adaptive and learning processes. Glutamate, the major excitatory neurotransmitter in the central nervous system (CNS), is of critical importance to these processes, acting at chemical synapses on two major classes of receptors - the metabotropic family of G-protein coupled receptors (mGluRs 1-8), and ionotropic family of ion channel forming receptors (iGluRs). The latter comprises the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), N-methyl-d-aspartate (NMDA) and kainate receptors. Despite similarities shared within this ion channel family, there exist clear structural and pharmacological differences which underlie their individual modes of action. This chapter provides a case history of ion channel lead optimisation, discusses ...
Figure 6. Translocation Mechanism and Directional Polarity(A) Schematic of a Rho translocation cycle in which six ATP molecules are hydrolyzed to move six nucleotides of RNA. Helicase subunits are illustrated as colored spheres. RNA is shown as a chain of white spheres spiraling out of the plane of the paper. Protein-RNA contacts are indicated by lines connecting the protein and RNA spheres; the black RNA sphere serves as a reference point and moves toward the viewer as the boxed red subunit transitions through six steps in the translocation cycle. A yellow star represents activation of the allosteric network that likely promotes hydrolysis. See also Movies S3-S6.(B) Schematics of Rho and E1 (chains A-F) illustrating their respective sequential ATP hydrolysis directions. Protein subunits are colored as inFigure 1. Nucleic acid phosphates observed in the structures are illustrated as bold orange circles, with the incoming phosphate shown as a dashed orange circle. Rectangles represent the two ...
Structural pathways are important because they provide insight into signaling mechanisms, help understand the mechanism of disease-related mutations, and assist in drug discovery. Ozbabacan et al. construct the IL-1 structural pathway and map oncogenic mutations and SNPs. They show that modeling of protein-protein interactions on a large scale can provide accurate, structural atom-level detail of signaling pathways in the human cell and help delineate the mechanism through which a mutation leads to disease.. Numerous approaches have been undertaken over the last 50 years in an effort to explain allostery. Chung-Jung Tsai and Ruth Nussinov survey points of view on allostery in a Perspective, synthesizing them via a mathematical model in order to obtain a coherent understanding of the question of how allostery works. They address this question from three standpoints: thermodynamics, free energy landscape of population shift, and structure; all with exactly the same allosteric descriptors.. ...
Allosteric MEK inhibitors represent the first pharmacologic inhibitors of the RAS-RAF-MEK-ERK pathway, with CI-1040 being the first to be tested in human clinical trials (13). Although the human efficacy of CI-1040 was likely limited due to poor drug-like properties and a lack of potency, this inhibitor provided preclinical proof-of-concept that targeting MEK can result in antitumor activity in preclinical models (14). This work led to the development of more potent allosteric inhibitors with improved properties, such as PD0325901 and ARRY142886/AZD6244, as well as a host of others that have demonstrated therapeutic efficacy in human clinical trials (reviewed in ref. 15). The most advanced MEK inhibitor, trametinib, was recently approved for the treatment of metastatic melanoma expressing BRAFV600E/K. In a phase III trial in patients with metastatic melanoma whose tumors express BRAFV600E/K, trametinib treatment resulted in a 22% response rate and 4.8 months median progression-free survival, ...
View and buy high purity VU 0424465 from Tocris Bioscience. Potent mGlu5 positive allosteric modulator and agonist; binds allosteric site with high affinity.
Domain Therapeutics is developing metabotropic glutamate receptor 3 negative allosteric modulators (mGluR3 NAM) for the treatment of various cancers.
BICYCLIC AZA COMPOUNDS AS MUSCARINIC M1 RECEPTOR ANTAGONISTS | FATTY ACID CONJUGATES OF QUETIAPINE, PROCESS FOR MAKING AND USING THE SAME | AMINOPYRIMIDINE KINASE INHIBITORS | SUBSTITUTED 4-ALKOXYPICOLINAMIDE ANALOGS AS MGLUR5 NEGATIVE ALLOSTERIC MODULATORS AND METHODS OF MAKING AND... | NOVEL COMPOUNDS |
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA Jr, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adao C, Jaramill J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2003) Gaussian 03. Gaussian, Inc., Pittsburgh, PAGoogle Scholar ...
One family, ccdAB, interferes with replication and transcription via interactions with gyrase. This family has been extensively studied in the last five years, leading to a detailed understanding on how the toxin CcdB poisons DNA-bound-gyrase and how the intrinsically disordered domain of the antitoxin CcdA is able to rejuvenated CcdB-poisoned gyrase. The latter proves to be an example on how intrinsically disordered proteins act in mechanistic terms and why intrinsic disorder is required in certain biochemical contexts.. Another family of TA modules, phd/doc, inhibit translation by interfering with the action of the ribosome. The phd/doc module of bacteriophage P1 is being used to study transcription regulation by conditional co-operativity. This is a novel regulatory mechanism used by bacteria that involves allosteric communication between two (partly) disordered protein domains. While such a form of allostery has been predicted based on theoretical arguments, our work provided the first ...
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Zvejniece L.; Vavers E.; Veinberg G.; Švalbe B.; Domracheva Ilona; Vilšķērsts R.; Dambrova M. Stereoselective pharmacological activity of 4,5-disubstituted piracetam derivatives, positive allosteric modulators of sigma-1 receptor. P.62 (OP42).. Abstract Book, Drug Discovery conference, Drug Discovery conference; Riga, Latvia: Riga, Latvia, 2015 ...
Covalent modification: Many if not most proteins are subjected to post-translational modifications which can affect enzyme activity through local or global shape changes, by promoting or inhibiting binding interaction of substrates and allosteric regulators, and even by changing the location of the protein within the cell. Proteins may be phosphorylated, acetylated, methylated, sulfated, glycosylated, amidated, hydroxylated, prenylated, myristolated, often in a reversible fashion. Some of these modifications are reversible. Regulation by phosphorylation through the action of kinases, and dephosphorylation by phosphates is extremely common. Control of phosphorylation state is mediated through signal transduction process starting at the cell membrane, leading to the activation or inhibition of protein kinases and phosphatases within the cell ...
Ernie Maynard asked: ,Is there a good enzyme kinetics news group out there??? ,I am interseted in allosteric interactions between proteins ,and the kinetics describing such systems Try the BTK-MCA news group (http://www.bio.net/hypermail/BTK-MCA/). Recently its been mostly advertisement and porn sites, but it isnt always like that and if you post some good messages theyll get responses. Occasionally (this month, for example) the PROTEIN-ANALYSIS news group has some relevant stuff (http://www.bio.net/hypermail/PROTEIN-ANALYSIS/9812/) Athel Email: athel at ibsm.cnrs-mrs.fr Site map: http://ir2lcb.cnrs-mrs.fr/~athel/sitemap.htm ...
Researchers from the University of Granada have discovered, for the first time, an allosteric interaction (that is, a regulation mechanism whereby enzymes can be activated or de-activated) between this protein, which forms ...
A. the active site is saturated with substrate B. there is a competitive inhibitor present C. there is a non-competitive inhibitor present D. the allosteric enzyme is locked in an inactive conformation E. all substrate has been converted to product ...
A. the active site is saturated with substrate B. there is a competitive inhibitor present C. there is a non-competitive inhibitor present D. the allosteric enzyme is locked in an inactive conformation E. all substrate has been converted to product ...
1. An allosteric enzyme. a) Is an enzyme molecule that is denatured too quickly. b) Possesses more than one active site. c) Is an enzyme molecule that binds with inhibitors only when present. d) Is an enzyme that changes shape to fit the substrate. e) Speeds up chemical reactions. 2. The number of molecules of substrates converted to product per enzyme molecule per second is called the…. a) Turnover number / kcat. b) Optimum number. c) Maximum reaction rate / Vmax. d) Michaelis-Menten Constant / Km. e) None of the above. 3. Fill in the blanks: Enzymes __________________ the free energies of reactants/products therefore ___________________ the equilibrium of the reaction.. a) Change/creating. b) Change/ increasing. c) Does not change/does not change. d) Does not change/changing. e) Increase/decreasing. 4. Which common example of an inhibitor is used as a medicinal drug?. a) Antibiotics. b) Panadol. c) Ascorbic acid. d) Aspirin. e) Lactate. 5. Enzymes act as. a) Protein molecules. b) Reaction ...
Get an answer for 1. The production of ATP is central to the survival of organisms. This production must be closely regulated to ensure that the needs of the organisms are being met. Considering the structure and function of enzymes and allosteric inhibitors, explain how the production of ATP is able to regulate itself. 2. Discuss the role of NAD+ and NADH in metabolism. Include in your discussion whether on not taking an NADH supplements would be helpful for physical activity. 3.Mr. Friedrichs lungs bra
The conversion of molecule S to product P has a Keq = 2.0. Two different, but related enzymes, A and B, can catalyze the reaction. The product P serves as an allosteric inhibitor of enzyme B, but not of enzyme A. A. 10 mM S is placed ...
Buy YM-01 (YM-1) (CAS 409086-68-6), a water soluble allosteric Hsp70 modulator; potent anti-tau agent. Join researchers using high quality YM-01 (YM-1) from…
Abstract: : Purpose:Transducin activation by rhodopsin has been shown under positive allosteric control (Wessling-Resnick and Johnson, JBC 262,3996 (1987)). The origin of this allosteric behavior has not been identified. Chemical cross-linking study (Hingorani, et al., JBC,259,6694 (1984)) suggested that transducin forms supermolecular structure as large as [Tαßγ]4 in solution. In this study, the role of the tetrameric [Tαßγ]4 on the allosteric behavior of transducin is investigated. Methods:Correlations of the tetrameric transducin [Tαßγ]4 and its binding to rhodopsin have been studied by analytical ultracentrifugation and chemical modification methods. Specific inhibitory effect of bovine serum albumin (Buzdygon and Leibman, JBC,259,14567,(1984)) on the allosteric binding of transducin was examined. Results:Ultracentrifugation study confirmed that transducin in solution is under equilibrium of [Tαßγ]4 and Tαßγ. Upon activation with Gpp(NH)p, these complexes dissociate into ...
Multiple allosteric sites on muscarinic receptors.: Proteins and small molecules are capable of regulating the agonist binding and function of G-protein coupled
Antigen uptake and processing by innate immune cells is crucial to initiate the immune response. Therein, the endocytic C-type lectin receptors serve as pattern recognition receptors, detecting pathogens by their glycan structures. Herein, we studied the carbohydrate recognition domain of Langerin, a C-type lectin receptor involved in the host defense against viruses such as HIV and influenza as well as bacteria and fungi. Using a combination of nuclear magnetic resonance and molecular dynamics simulations, we unraveled the molecular determinants underlying cargo capture and release encoded in the receptor architecture. Our findings revealed receptor dynamics over several time scales associated with binding and release of the essential cofactor Ca(2+) controlled by the coupled motions of two loops. Applying mutual information theory and site-directed mutagenesis, we identified an allosteric intradomain network that modulates the Ca(2+) affinity depending on the pH, thereby promoting fast ligand ...
Allosteric transmission of information between distant sites in biological macromolecules often involves collective transitions between active and inactive conformations. Nuclear magnetic resonance (NMR) spectroscopy can yield detailed information on these dynamics. In particular, relaxation dispersion techniques provide structural, dynamic, and mechanistic information on conformational transitions occurring on the millisecond to microsecond timescales. In this review, we provide an overview of the theory and analysis of Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion NMR experiments and briefly describe their application to the study of allosteric dynamics in the homeodomain from the PBX transcription factor (PBX-HD). CPMG NMR data show that local folding (helix/coil) transitions in one part of PBX-HD help to communicate information between two distant binding sites. Furthermore, the combination of CPMG and other spin relaxation data show that this region can also undergo local ...
TY - JOUR. T1 - Differences in the allosteric properties of pure low and high phosphate forms of phosphofructokinase from rat liver.. AU - Sakakibara, R.. AU - Uyeda, K.. PY - 1983/7/25. Y1 - 1983/7/25. N2 - Low phosphate and high phosphate forms of phosphofructokinase (Furuya, E., and Uyeda, K. (1980) J. Biol. Chem. 255, 11656-11659) from rat liver were purified to homogeneity and various properties were compared. The specific activities of these enzymes and their electrophoretic mobilities on polyacrylamide in sodium dodecyl sulfate are the same. A limited tryptic digestion yields products with no change in the enzyme activity but with a reduction in the molecular weight of about 2000. Both low and high phosphate enzymes can be phosphorylated by the catalytic subunit of cAMP-dependent protein kinase, and approximately twice as much [32P]phosphate is incorporated into the low phosphate than the high phosphate enzyme. A comparison of their allosteric kinetic properties reveal that the high ...
Metabotropic glutamate receptors (mGluRs) play key roles in the modulation of many synapses. Chloride (Cl(-)) is known to directly bind and regulate the function of different actors of neuronal activity, and several studies have pointed to the possible modulation of mGluRs by Cl(-). Herein, we demonstrate that Cl(-) behaves as a positive allosteric modulator of mGluRs. For example, whereas glutamate potency was 3.08 ± 0.33 μM on metabotropic glutamate (mGlu) 4 receptors in high-Cl(-) buffer, signaling activity was almost abolished in low Cl(-) in cell-based assays. Cl(-) potency was 78.6 ± 3.5 mM. Cl(-) possesses a high positive cooperativity with glutamate (Hill slope ≈6 on mGlu4), meaning that small variations in [Cl(-)] lead to large variations in glutamate action. Using molecular modeling and mutagenesis, we have identified 2 well-conserved Cl(-) binding pockets in the extracellular domain of mGluRs. Moreover, modeling of activity-dependent Cl(-) variations at GABAergic synapses ...
Detail záznamu - Allosteric Modulation of Muscarinic Acetylcholine Receptors - Detail záznamu - Knihovna Akademie věd České republiky
Lancet, D; Licht, A; Schechter, I; and Pecht, I, "Hapten-induced allosteric transition in the light chain dimer of an immunoglobulin." (1977). Subject Strain Bibliography 1977. 708 ...
When freshwater turtles acclimatize to winter hibernation, there is a gradual transition from aerobic to anaerobic metabolism, which may require adjustments of blood O2 transport before turtles become anoxic. Here, we report the effects of protons, anionic cofactors, and temperature on the O2-binding properties of isolated hemoglobin (Hb) isoforms, HbA and HbD, in the turtle Trachemys scripta. We determined the primary structures of the constituent subunits of the two Hb isoforms, and we related the measured functional properties to differences in O2 affinity between untreated hemolysates from turtles that were acclimated to normoxia and anoxia. Our data show that HbD has a consistently higher O2 affinity compared with HbA, whereas Bohr and temperature effects, as well as thiol reactivity, are similar. Although sequence data show amino acid substitutions at two known β-chain ATP-binding site positions, we find high ATP affinities for both Hb isoforms, suggesting an alternative and stronger binding site
ATP binding cassette (ABC) transporters mediate vital transport processes in every living cell. ATP hydrolysis, which fuels transport, displays positive cooperativity in numerous ABC transporters. In particular, heterodimeric ABC exporters exhibit pronounced allosteric coupling between a catalytically impaired degenerate site, where nucleotides bind tightly, and a consensus site, at which ATP is hydrolyzed in every transport cycle. Whereas the functional phenomenon of cooperativity is well described, its structural basis remains poorly understood. Here, we present the apo structure of the heterodimeric ABC exporter TM287/288 and compare it to the previously solved structure with adenosine 5-(β,γ-imido)triphosphate (AMP-PNP) bound at the degenerate site. In contrast to other ABC exporter structures, the nucleotide binding domains (NBDs) of TM287/288 remain in molecular contact even in the absence of nucleotides, and the arrangement of the transmembrane domains (TMDs) is not influenced by ...
PRF readers can get free access to a selected Journal of Pain paper each month, thanks to the American Pain Society. Get the free full text of the selection from the November 2017 issue here.. ...
Red blood cell-dependent hypoxic vasodilation is largely mediated via the delivery of NO through S-nitrosohemoglobin (Hb-SNO). Hb-SNO is regulated through allosteric and redox mechanisms that are not well understood. Part One of this dissertation explores the biochemical features of Hb micropopulations suggested to be involved in Hb-SNO synthesis. An NO-liganded mixed valency micropopulation was synthesized in vitro and identified spectroscopically as a ferric nitrosyl species (Fe(III)NO). Remarkably, this species was found to undergo a reaction that couples heme reduction and S-nitrosylation of β93C. The biochemical properties of this species were found to resemble those of Hb valency hybrids (VHys) identified by others in previous work. The similarities between the two species are discussed, and a model for Hb-SNO formation, including the putative identification of the intermediates involved, is proposed. Part Two explores the insights provided by this chemistry as it is relevant to human ...
Zhang L, Balan G, Barreiro G, Boscoe BP, Chenard LK, Cianfrogna J, Claffey MM, Chen L, Coffman KJ, Drozda SE, Dunetz JR, Fonseca KR, Galatsis P, Grimwood S, Lazzaro JT, Mancuso JY, Miller EL, Reese MR, Rogers BN, Sakurada I, Skaddan M, Smith DL, Stepan AF, Trapa P, Tuttle JB, Verhoest PR, Walker DP, Wright AS, Zaleska MM, Zasadny K, Shaffer CL. Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator. J Med Chem. 2014 Feb 13; 57(3):861-77 ...
Preface xix. Acknowledgments xxi. PART 1 BASIC PRINCIPLES 1. 1. Thermodynamics 3. 2. Four Basic Quantum Mechanical Models of Nuclear and Electronic Motion: A Synopsis 35. 3. Molecular Structure and Interactions 51. 4. Water and the Hydrophobic Effect 77. PART 2 STATISTICAL MECHANICS: THE MOLECULAR BASIS OF THERMODYNAMICS 91. 5. The Molecular Partition Function 93. 6. System Ensembles and Partition Functions 111. 7. Sampling Molecular Systems with Simulations 137. PART 3 BINDING TO MACROMOLECULES 161. 8. Binding Equilibria 163. 9. Thermodynamics of Molecular Interactions 185. 10. Elements of Statistical Mechanics of Liquids and Solutions 197. 11. Analysis of Binding Equilibria in Terms of Partition Functions 213. 12. Coupled Equilibria 223. 13. Allosteric Function 239. 14. Charged Groups: Binding of Hydrogen Ions, Solvation, and Charge-Charge Interactions 255. PART 4 CONFORMATIONAL STABILITY AND CONFORMATION CHANGE 277. 15. Some Elements of Polymer Physics 279. 16. Helix-Coil Equilibria ...
Data Availability StatementAll components and data can be purchased in the manuscript. vitro appearance of development elements secreted by hAD-MSCs in hAD-MSC-conditioned mass media (hAD-MSC-CM) was examined by ELISA. Sixty feminine SD TG-101348 enzyme inhibitor rats had been split into control, POI, and hAD-MSC-CM-treated groupings, and hAD-MSC-CM was injected in to the bilateral ovaries of POI rats. After hAD-MSC transplantation or hAD-MSC-CM shot, serum sex hormone amounts, estrous cycles, ovarian pathological adjustments, follicle matters, granulosa cell (GC) apoptosis, and Bcl-2, Bax, and VEGF appearance in ovaries had been examined. Outcomes PKH26-labeled hAD-MSCs homed to ovaries after transplantation mainly. hAD-MSC transplantation decreased ovarian damage and improved ovarian function in rats with POI. Transplanted hAD-MSCs had been only situated in the interstitium of ovaries, than in follicles rather, and didnt exhibit the normal markers of GCs and oocytes, that are FSHR and ZP3, ...
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Current research is directed towards the discovery of small molecule protein kinase inhibitors targeting signaling and cell cycle proteins involved in tumor proliferation. Rather than blocking ATP binding, we are focused on the development of very selective inhibitors by targeting protein-protein interactions involved in allosteric regulation of kinase activity and other non-catalytic functions of such enzymes.. The McInnes laboratory has developed the REPLACE strategy in order to more effectively target PPIs in general and have validated this approach with several kinase targets. Promising compounds obtained through application of REPLACE are being developed further by medicinal chemistry, cellular phenotypic characterization and testing in preclinical tumor models. McInnes has recently started a spin-off company called PPI Pharmaceuticals, LLC in order to exploit promising compounds discovered in his academic laboratory.. ...
VCH-916 is a novel allosteric inhibitor of HCV NS5B polymerase. The RNA-dependent RNA polymerase (NS5B) of HCV is one of the attractive validated targets for development of new drugs to block HCV infection. VCH-916 is currently being evaluated for safety/tolerability, pharmacokinetics and anti-viral efficacy in chronically infected HCV patient ...
The serotonin transporter (SERT) controls synaptic serotonin levels and is the primary target for antidepressants, including selective serotonin reuptake inhibitors (e.g. (S)-citalopram) and tricyclic antidepressants (e.g. clomipramine). In addition to a high affinity binding site, SERT possesses a low affinity allosteric site for antidepressants. Binding to the allosteric site impedes dissociation of antidepressants from the high affinity site, which may enhance antidepressant efficacy. Here we employ an induced fit docking/molecular dynamics protocol to identify the residues that may be involved in the allosteric binding in the extracellular vestibule located above the central substrate binding (S1) site. Indeed, mutagenesis of selected residues in the vestibule reduces the allosteric potency of (S)-citalopram and clomipramine. The identified site is further supported by the inhibitory effects of Zn(2+) binding in an engineered site and the covalent attachment of ...
1. 1. Pyruvate kinase of the adductor muscle of the sea mussel displays an absolute requirement for Mg2+ or Mn2+. By the use of Ca2+ or Zn2+ no enzyme activity is obtained. 2. 2. In the presence of Mn2+, in contrast to Mg2+, always hyperbolic substrate saturation curves are obtained. 3. 3. ... read more There is evidence that Mn2+ not only acts by forming an ADP-Mn2+ complex, but also as an allosteric activator. 4. 4. Ca2+ is a strong inhibitor but the enzyme becomes less sensitive to this inhibition when Mg2+ is replaced for Mn2. show less ...
Here a novel electrochemical method for the rapid detection of anti-HIV antibodies in serum is presented. The novelty lies in the combination of allosteric enzymes and coulometry to yield a fast, simple and reliable HIV diagnostic method. We have used a previously developed β-galactosidase enzyme that is efficiently activated by anti-HIV antibodies directed against a major B-cell epitope of the gp41 glycoprotein. When these antibodies bind the enzyme, the 3D conformation changes positively affecting the performance of the active site and, consequently, the enzyme activity is stimulated. Using 4-aminophenyl β-d-galactopyranoside (PAPG) as substrate yields p-aminophenol (PAP), which is reversibly oxidised at a very mild potential, ca. 0.37 V vs. Ag/AgCl over a range of electrode materials within the working pH range of β-galactosidase. In the present case, photolithographically produced microelectrode arrays resulted in a detection limit of 4 μM for 4-aminophenol (PAP). The presence of ...
J Exp Biol. 2013 Nov 15;216(Pt 22):4264-71. doi: 10.1242/jeb.091397. Research Support, N.I.H., Extramural; Research Support, Non-U.S. Govt
TY - JOUR. T1 - Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation. AU - Koole, Cassandra. AU - Wootten, Denise. AU - Simms, John. AU - Valant, Celine. AU - Miller, Laurence J. AU - Christopoulos, Arthur. AU - Sexton, Patrick. PY - 2011. Y1 - 2011. N2 - The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and a major therapeutic target for the treatment of diabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides that interact with the receptor, including full length (1-37) and truncated (7-37) forms of GLP-1 that can exist in an amidated form (GLP-1(1-36)NH(2) and GLP-1(7-36)NH(2)), and the related peptide oxyntomodulin. In addition, the GLP-1R possesses exogenous agonists, including exendin-4, and the allosteric modulator, compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline). The complexity of ...
TY - JOUR. T1 - Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors. AU - Arias, H. R.. AU - Xing, H.. AU - MacDougall, K.. AU - Blanton, M. P.. AU - Soti, F.. AU - Kern, W. R.. PY - 2009/5/1. Y1 - 2009/5/1. N2 - Background and purpose: Benzylidene-anabaseines (BAs) are partial agonists of the α7 nicotinic acetylcholine receptor (nAChR) but their mechanism(s) of action are unknown. Our study explores several possibilities, including direct interactions of BAs with the nAChR channel. Experimental approach: Functional and radioligand-binding assays were used to examine the interaction of two BA analogues, 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) and Its primary metabolite 3-(4-hydroxy-2-methoxybenzylidene)anabaseine (4OH-DMXBA) with both agonist and non-competitive antagonist (NCA)-bindlng sites on muscle-type nAChRs. Key results: Both BAs non-competitively inhibited ACh activation of human fetal muscle nAChRs and ...
Carroll, F. (2008). Antagonists at Metabotropic Glutamate Receptor Subtype 5 Structure Activity Relationships and Therapeutic Potential for Addiction: Addiction Reviews 2008. Annals of the New York Academy of Sciences, 1141, 221-232 ...

RCSB PDB 









- 1GLF: CRYSTAL STRUCTURES OF ESCHERICHIA COLI GLYCEROL KINASE AND THE MUTANT A65T IN AN INACTIVE TETRAMER:...RCSB PDB - 1GLF: CRYSTAL STRUCTURES OF ESCHERICHIA COLI GLYCEROL KINASE AND THE MUTANT A65T IN AN INACTIVE TETRAMER:...

... the crystal structures reveal conformational changes with implications for allosteric regulation. ... CONFORMATIONAL CHANGES AND IMPLICATIONS FOR ALLOSTERIC REGULATION. ...
more infohttp://www.rcsb.org/pdb/explore/derivedData.do?structureId=1GLF

Allosteric regulation - WikipediaAllosteric regulation - Wikipedia

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 ...
more infohttps://en.wikipedia.org/wiki/Homotropic_allosteric_interaction

Allosteric regulation - WikipediaAllosteric regulation - Wikipedia

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 ...
more infohttps://en.m.wikipedia.org/wiki/Allosteric

Allosteric regulation of … - University of Gothenburg, Sweden 
							
							
						
					
				
			Allosteric regulation of … - University of Gothenburg, Sweden

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. ...
more infohttps://www.gu.se/english/research/publication?publicationId=199388

Prepaying the entropic cost for allosteric regulation in KIX | PNASPrepaying the entropic cost for allosteric regulation in KIX | PNAS

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 ...
more infohttp://www.pnas.org/content/early/2014/07/02/1405831111

Engineering allosteric regulation in protein kinases | Science SignalingEngineering allosteric regulation in protein kinases | Science Signaling

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 ...
more infohttps://stke.sciencemag.org/content/11/555/eaar3250/tab-figures-data

Allosteric regulation - WikipediaAllosteric regulation - Wikipedia

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 ...
more infohttps://en.wikipedia.org/wiki/Allosteric_regulation

Postdoctoral Position - Allosteric Regulation in the KDM5 Family of Histone Demethylases | ISMARPostdoctoral Position - Allosteric Regulation in the KDM5 Family of Histone Demethylases | ISMAR

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 ...
more infohttp://www.weizmann.ac.il/ISMAR/positions/postdoctoral-position-allosteric-regulation-kdm5-family-histone-demethylases

PLOS Computational Biology: Binding Leverage as a Molecular Basis for Allosteric RegulationPLOS Computational Biology: Binding Leverage as a Molecular Basis for Allosteric Regulation

... 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 ...
more infohttps://journals.plos.org/ploscompbiol/article/figure?id=10.1371/journal.pcbi.1002148.t002

Quiz & Worksheet - Allosteric Regulation of Enzymes | Study.comQuiz & Worksheet - Allosteric Regulation of Enzymes | Study.com

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 ...
more infohttps://study.com/academy/practice/quiz-worksheet-allosteric-regulation-of-enzymes.html

Allosteric regulation of rhomboid intramembrane proteolysis | The EMBO JournalAllosteric regulation of rhomboid intramembrane proteolysis | The EMBO Journal

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. ...
more infohttp://emboj.embopress.org/content/33/17/1869?ijkey=dcc7e9b7a040c6b653ec87d4358438ba85f2c5b6&keytype2=tf_ipsecsha

Targeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer | Cancer ResearchTargeting PARP-1 Allosteric Regulation Offers Therapeutic Potential against Cancer | Cancer Research

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 ...
more infohttp://cancerres.aacrjournals.org/content/74/1/31

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 ... 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 ...
more infohttps://www.ncbi.nlm.nih.gov/pubmed/24172889

Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation | Science SignalingReciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation | Science Signaling

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 ...
more infohttps://stke.sciencemag.org/content/7/347/ra98.abstract

Molecules | Free Full-Text | Theoretical Study on the Allosteric Regulation of an Oligomeric Protease from Pyrococcus...Molecules | Free Full-Text | Theoretical Study on the Allosteric Regulation of an Oligomeric Protease from Pyrococcus...

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 ...
more infohttps://www.mdpi.com/1420-3049/19/2/1828

Novel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit | eLifeNovel ATP-cone-driven allosteric regulation of ribonucleotide reductase via the radical-generating subunit | eLife

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 ...
more infohttps://elifesciences.org/articles/31529

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 ... 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 ...
more infohttp://cancerres.aacrjournals.org/content/early/2017/12/28/0008-5472.CAN-17-2876

Allosteric regulation | definition of Allosteric regulation by Medical dictionaryAllosteric regulation | definition of Allosteric regulation by Medical dictionary

What is Allosteric regulation? Meaning of Allosteric regulation medical term. What does Allosteric regulation mean? ... Looking for online definition of Allosteric regulation in the Medical Dictionary? Allosteric regulation explanation free. ... Related to Allosteric regulation: feedback inhibition, Allosteric enzyme, covalent modification. allosteric. [al″o-ster´ik] ... allosteric. (redirected from Allosteric regulation). Also found in: Dictionary, Encyclopedia, Wikipedia. ...
more infohttps://medical-dictionary.thefreedictionary.com/Allosteric+regulation

Allosteric regulation of the adenosine triphosphate phosphoribosyltransferase from campylobacter jejuniAllosteric regulation of the adenosine triphosphate phosphoribosyltransferase from campylobacter jejuni

In the long form ATP-PRT histidine binds to the allosteric site at the regulatory domain, but the exact nature of the ... In chapter 4 a potential intramolecular communication pathway from the allosteric to the active site is probed by the ... ATP-PRT activity is modulated by two layers of regulation: active site inhibition by adenosine monophosphate, which reflects ... although this ligand is still able to bind at the allosteric site, which is consistent with the involvement of R216 in the ...
more infohttps://ir.canterbury.ac.nz/handle/10092/10799

Allosteric Regulation of Glycogen Synthase - Asociación Española de Enfermos de Glucogenosis (AEEG)Allosteric Regulation of Glycogen Synthase - Asociación Española de Enfermos de Glucogenosis (AEEG)

Allosteric Regulation of Glycogen Synthase Controls Glycogen Synthesis in Muscle. SUMMARY. Glycogen synthase (GS), a key enzyme ... Our study provides genetic evidence that allosteric activation of GS is the primary mechanism by which insulin promotes muscle ... Here we identify a residue that plays an important role in the allosteric activation of GS by G6P. ... mainly due to the complex interplay between multiple phosphorylation sites and allosteric effectors. ...
more infohttp://www.glucogenosis.org/2015/10/26/allosteric-regulation-of-glycogen-synthase/

Allosteric RegulationAllosteric Regulation

Because AMP is an allosteric regulator that signals a low energy state in cells ---------, ... It does use some Fructose-6-P from the pathway, but Fructose-2,6-bisP is strictly an allosteric regulator of PFK-1. ...
more infohttp://www2.csudh.edu/nsturm/CHE452/05_Allosteric%20Regulation.htm

Get PDF - Sequence of the pckA gene of Escherichia coli K-12: relevance to genetic and allosteric regulation and homology of E....Get PDF - Sequence of the pckA gene of Escherichia coli K-12: relevance to genetic and allosteric regulation and homology of E....

... relevance to genetic and allosteric regulation and homology of E. coli phosphoenolpyruvate carboxykinase with the enzymes from ... Sequence of the pck a gene of escherichia coli k 12 relevance to genetic and allosteric regulation and homology of escherichia ... Sequence of the pckA gene of Escherichia coli K-12: relevance to genetic and allosteric regulation and homology of E. coli ... Sequence of the pckA gene of Escherichia coli K-12: relevance to genetic and allosteric regulation and homology of E. coli ...
more infohttps://eurekamag.com/research/002/219/002219080.php

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

committed step in a pathway Allosteric regulation (mechanism) Binding of ATP to a non-substrate (allosteric) site on the enzyme ... 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 ...
more infohttps://www.coursehero.com/file/6123813/L0710ap/

Inserm - On the role of the difference in surface tensions involved in the allosteric regulation of NHE-1 induced by low to...Inserm - On the role of the difference in surface tensions involved in the allosteric regulation of NHE-1 induced by low to...

It is cooperatively activated by intracellular protons, and this allosteric regulation is modulated by the biophysical ... The purpose of this study was to develop the relationship between membrane surface tension, and the allosteric balance of a ... fluid phase endocytosis and the allosteric equilibrium constant of the transporter. We then used the experimental data ... published on the effects of osmotic pressure and membrane modification on the NHE-1 allosteric constant to fit these equations ...
more infohttps://www.hal.inserm.fr/inserm-00871709

Definition of allosteric regulation - Chemistry DictionaryDefinition of allosteric regulation - Chemistry Dictionary

Definition of allosteric regulation. 1) Allosteric regulation is the regulation of the activity of allosteric enzymes. (See ...
more infohttp://www.chemistry-dictionary.com/definition/allosteric+regulation.php
  • 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)
  • 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)
  • 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)
  • Here, we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. (aacrjournals.org)
  • The purpose of this study was to develop the relationship between membrane surface tension, and the allosteric balance of a mechanosensitive transporter such as NHE-1. (inserm.fr)
  • Therefore, we took this phenomenon into account in this study and developed a set of relations between the mean surface tension, membrane asymmetry, fluid phase endocytosis and the allosteric equilibrium constant of the transporter. (inserm.fr)
  • It is cooperatively activated by intracellular protons, and this allosteric regulation is modulated by the biophysical properties of the plasma membrane and related lipid environment. (inserm.fr)
  • The sequential model of allosteric regulation holds that subunits are not connected in such a way that a conformational change in one induces a similar change in the others. (wikipedia.org)
  • The morpheein model of allosteric regulation is a dissociative concerted model. (wikipedia.org)
  • The required oligomer disassembly step differentiates the morpheein model for allosteric regulation from the classic MWC and KNF models. (wikipedia.org)
  • On the role of the difference in surface tensions involved in the allosteric regulation of NHE-1 induced by low to mild osmotic pressure, membrane tension and lipid asymmetry. (inserm.fr)
  • The fine regulation of these two conflicting actions of thrombin is required to maintain the homeostasis. (aronorabio.com)