This article does not cite any references or sources. (August 2007) Please help improve this article by adding citations to reliable sources. Unverifiable material may be challenged and removed.

It has been suggested that Heterotropic allosteric modulator be merged into this article or section. (Discuss)

It has been suggested that Homotropic allosteric modulator be merged into this article or section. (Discuss)

It has been suggested that Allosteric enzyme be merged into this article or section. (Discuss)

In biochemistry, allosteric regulation is the regulation of an enzyme or protein by binding an effector molecule at the protein's allosteric site (that is, a site other than the protein's active site). Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors. The term allostery comes from the Greek allos, "other," and stereos, "space," referring to the regulatory site of an allosteric protein's being separate from its active site. Allosteric regulation is a natural example of feedback control. Image File history File links Question_book-3. ... Image File history File links Mergefrom. ... In biochemistry, a heterotropic allosteric interaction is one in which the activity of an allosteric protein is regulated by a molecule other than the proteins substrate. ... Image File history File links Mergefrom. ... In biochemistry, a homotrophic allosteric interaction is one in which the activity of an allosteric protein is regulated by its substrate. ... Image File history File links Mergefrom. ... The word allosteric comes from the Greek allos,other and stereos,shape. This denotes the fact that allosteric enzymes change shape, or conformation, on binding of the modulator. ... Biochemistry (from Greek: , bios, life and Egyptian kēme, earth[1]) is the study of the chemical processes in living organisms. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... An effector is a small molecule that binds to a protein and thereby alters the activity of that protein. ... The active site of an enzyme is the binding site where catalysis occurs. ... For the superhero, see Feedback (Dark Horse Comics). ...

Models of allosteric regulation

Most allosteric effects can be explained by the concerted MWC model put forth by Monod, Wyman, and Changeux,^[1] or by the sequential model described by Koshland, Nemethy, and Filmer.^[2] Both postulate that enzyme subunits exist in one of two conformations, tensed (T) or relaxed (R), and that relaxed subunits bind substrate more readily than those in the tense state. The two models differ most in their assumptions about subunit interaction and the preexistence of both states. In biochemistry, the MWC model refers to the Concerted model (by opposition to the Sequential model, or KNF model) of allosteric transition, which was proposed by Jean-Pierre Changeux based on his PhD experiements, and described by Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux. ... Jacques Lucien Monod (February 9, 1910 – May 31, 1976) was a French biologist and a Nobel Prize Winner in Physiology or Medicine in 1965. ... Jean-Pierre Changeux (born in Domont, France, April 7, 1936) is a French neuroscientist, who researched many different areas of biology in his life, from the structure and function of proteins, to the early development of the nervous system. ... The sequential model (also known as the KNF model) is a theory that describes co-operativity of proteins subunits. ... In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles (or coassembles) with other protein molecules to form a multimeric or oligomeric protein. ... Conformation generally means structural arrangement. ...

Concerted model

The concerted model of allostery, also referred to as the symmetry model or MWC- model, postulates that enzyme subunits are connected in such a way that a conformational change in one subunit is necessarily conferred to all other subunits. Thus all subunits must exist in the same conformation. The model further holds that in the absence of any ligand (substrate or otherwise), the equilibrium favors one of the conformational states, T or R. The equilibrium can be shifted to the R or T state through the binding of one ligand (the allosteric effector or ligand) to a site that is different from the active site (the allosteric site). It has been suggested that this article or section be merged with ligand. ...

Sequential model

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. Thus, all enzyme subunits do not necessitate the same conformation. Moreover, the sequential model dictates that molecules of substrate bind via an induced fit protocol. In general, when a subunit randomly collides with a molecule of substrate, the active site essentially forms a glove around its substrate. While such an induced fit converts a subunit from the tensed state to relaxed state, it does not propagate the conformational change to adjacent subunits. Instead, substrate-binding at one subunit only slightly alters the structure of other subunits so that their binding sites are more receptive to substrate. To summarize: Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... Look up substrate in Wiktionary, the free dictionary. ...

• subunits need not exist in the same conformation
• molecules of substrate bind via induced-fit protocol
• conformational changes are not propagated to all subunits
• substrate-binding causes increased substrate affinity in adjacent subunits

Allosteric activation and inhibition

Activation

Allosteric activation, such as the binding of oxygen molecules to hemoglobin, occurs when the binding of one ligand enhances the attraction between substrate molecules and other binding sites. With respect to hemoglobin, oxygen is effectively both the substrate and the effector. The allosteric, or "other," site is the active site of an adjoining protein subunit. The binding of oxygen to one subunit induces a conformational change in that subunit that interacts with the remaining active sites to enhance their oxygen affinity. General Name, symbol, number oxygen, O, 8 Chemical series nonmetals, chalcogens Group, period, block 16, 2, p Appearance colorless (gas) pale blue (liquid) Standard atomic weight 15. ... Structure of hemoglobin. ... For other uses, see Substrate. ... The active site of an enzyme is the binding site where catalysis occurs. ... In structural biology, a protein subunit or subunit protein is a double protein molecule that assembles (or coassembles) with other protein molecules to form a multimeric or oligomeric protein. ...

Inhibition

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.[1] In chemistry, a ligand is an atom, ion, or molecule (see also: functional group) that generally donates one or more of its electrons through a coordinate covalent bond to, or shares its electrons through a covalent bond with, one or more central atoms or ions (these ligands act as a... 2,3-Bisphosphoglycerate (2,3-BPG, also known as 2,3-diphosphoglycerate or 2,3-DPG) is a three carbon isomer of the glycolytic intermediate 1,3-bisphosphoglycerate. ...

Another good example is strychnine, a convulsant poison, acting as an allosteric inhibitor of glycine. 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. Strychnine thus inhibits the action of an inhibitory transmitter, causing convulsions. Strychnine (pronounced (British, U.S.), or (U.S.)) is a very toxic (LD50 = 10 mg approx. ... This article is about epileptic seizures. ... For the plant, see Glycine (plant). ... Illustration of the major elements in a prototypical synapse. ... Chemical structure of D-aspartic acid, a common amino acid neurotransmitter. ... Subclasses & Infraclasses Subclass †Allotheria* Subclass Prototheria Subclass Theria Infraclass †Trituberculata Infraclass Metatheria Infraclass Eutheria Mammals (class Mammalia) are warm-blooded, vertebrate animals characterized by the presence of sweat glands, including those that produce milk, and by the presence of: hair, three middle ear bones used in hearing, and a neocortex... The Spinal cord nested in the vertebral column. ... The brain stem is the lower part of the brain, adjoining and structurally continuous with the spinal cord. ... The Glycine receptor is one of the most widely distributed inhibitory receptors in the Central nervous system. ... Look up affinity in Wiktionary, the free dictionary. ...

Types of effectors

Many allosteric proteins are regulated by their substrate; such a substrate is considered a homotropic allosteric modulator, and is typically an activator. Non-substrate regulatory molecules are called heterotropic allosteric modulators and can be either activators or inhibitors. In biochemistry, a homotrophic allosteric interaction is one in which the activity of an allosteric protein is regulated by its substrate. ... In biochemistry, a heterotropic allosteric interaction is one in which the activity of an allosteric protein is regulated by a molecule other than the proteins substrate. ...

Some allosteric proteins can be regulated by their substrates and by other molecules, as well. Such proteins are capable of both homotropic and heterotropic interactions.

Pharmacology

Allosteric modulation of a receptor results from the binding of allosteric modulators at a different site (regulatory site) other than of the endogenous ligand (orthosteric ligand) and enhances or inhibits the effects of the endogenous ligand. Normally acts by causing conformational change in receptor molecule which results in a change in the binding affinity of the ligand. In this way allosteric ligands “modulates” its activation by a primary “ligand” and can be thought to act like a dimmer switch in an electrical circuit, adjusting the intensity of the receptor’s activation. In chemistry and biochemistry, a dissociation constant or an ionization constant is a specific type of equilibrium constant used for reversible reactions or processes. ...

The anti-anxiety drugs Valium, Xanax, Librium and Ativan, for example, “potentiates” or turn up the activity of the benzodiazepine receptor when it binds to its primary ligand, the neurotransmitter gamma-aminobutyric acid (GABA). Diazepam, brand names: Valium, Seduxen, in Europe Apozepam, is a 1,4-benzodiazepine derivative, which possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. ... Alprazolam, is an anxiolytic benzodiazepine used to treat anxiety disorders. ... Chlordiazepoxide (Trade name: Librium) was the first benzodiazepine to be made commercially available. ... Lorazepam is classified as a sedative-hypnotic and a member of the group of drugs known as benzodiazepines. ... Synergy (from the Greek synergos, συνεργός meaning working together, circa 1660) refers to the phenomenon in which two or more discrete influences or agents acting together create an effect greater than that predicted by knowing only the separate effects of the individual agents. ... The GABAA receptor is one of two ligand-gated ion channels responsible for mediating the effects of Gamma-Amino Butyric Acid (GABA), the major inhibitory neurotransmitter in the brain. ... Gaba may refer to: Gabâ or gabaa (Philippines), the concept of negative karma of the Cebuano people GABA, the gamma-amino-butyric acid neurotransmitter GABA receptor, in biology, receptors with GABA as their endogenous ligand Gaba 1 to 1, an English conversational school in Japan Marianne Gaba, a US model...

Allosteric sites as drug targets

Allosteric sites may represent a novel drug target.There are a number of advantages in using allosteric modulators as preferred therapeutic agents over classic orthosteric ligands. For example, GPCR allosteric binding sites have not faced the same evolutionary pressure as orthosteric sites to accommodate an endogenous ligand so are more diverse.^[3] Therefore greater GPCR selectivity may be obtained by targeting allosteric sites.^[3]This is particularly useful for GPCRs where selective orthosteric therapy has been difficult because of sequence conservation of the orthosteric site across receptor subtypes.^[4]Also these modulators is a decreased potential for toxic effects, since modulators with limited co-operativity will have a ceiling level to their effect, irrespective of the administered dose.^[3] Another type of pharmacological selectivity that is unique to allosteric modulators is based on cooperativity. An allosteric modulator may display neutral cooperativity with an orthosteric ligand at all subtypes of a given receptor except the subtype of interest, which is termed absolute subtype selectivity.^[4] If an allosteric modulator does not possess appreciable efficacy, it can provide another powerful therapeutic advantage over orthosteric ligands, namely, the ability to selectively tune up or down tissue responses only when the endogenous agonist is present.^[4] In medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed. ... In cell biology, G-protein-coupled receptors, also known as GPCR, seven transmembrane receptors, heptahelical receptors, or 7TM receptors, are a class of transmembrane receptors. ...

See also

• Cooperative binding
• Enzyme kinetics

In biochemistry, a macromolecule has cooperative binding if when binding a ligand, the affinity of the ligand for the molecule changes depending on the amount of ligand already bound. ... Dihydrofolate reductase from with its two substrates, dihydrofolate (right) and NADPH (left), bound in the active site. ...

References