- Allosteric regulation
biochemistry, allosteric regulation is the regulation of an enzymeor other proteinby 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 "stere", "space," referring to the regulatory site of an allosteric protein's being separate from its active site. Allosteric regulations are natural example of control loops, such as feedback from downstream products or feedforwardfrom upstream substrates.
Models of allosteric regulation
Most allosteric effects can be explained by the "concerted"
MWC modelput forth by Monod, Wyman, and Changeux, [J. Monod, J. Wyman, J.P. Changeux. (1965). On the nature of allosteric transitions:A plausible model. "J. Mol. Biol.", May;12:88-118.] or by the sequential modeldescribed by Koshland, Nemethy, and Filmer. [D.E. Jr Koshland, G. Némethy, D. Filmer (1966) Comparison of experimental binding data and theoretical models in proteins containing subunits. "Biochemistry". Jan;5(1):365-8] 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.
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).
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 fitprotocol. 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:
* 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
"Allosteric activation", such as the binding of
oxygenmolecules 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.
"Allosteric inhibition" occurs when the binding of one
liganddecreases 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. [http://template.bio.warwick.ac.uk/staff/dhodgson/dnacomp/boolean/allosteric.gif]
Another good example is
strychnine, a convulsant poison, acting as an allosteric inhibitor of glycine. Glycine is a major post-synaptic inhibitory neurotransmitterin mammalian spinal cordand brain stem. Strychnine acts at a separate binding site on the glycine receptorin an allosteric manner; i.e. its binding lowers the affinityof the glycine receptor for glycine. Strychnine thus inhibits the action of an inhibitory transmitter, causing convulsions.
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.
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.
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. It normally acts by causing a
conformational changein a receptor molecule which results in a change in the binding affinity of the ligand. In this way an allosteric ligand “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.
The anti-anxiety drugs
Valium, Xanax, Libriumand Ativan, for example, “potentiates” or turn up the activity of the neurotransmitter gamma-aminobutyric acid ( GABA) when it binds to its primary ligand, the benzodiazepine receptor. More recent examples of drugs which allosterically modulate their drug targets include Cinacalcetand Maraviroc
Allosteric sites as drug targets
Allosteric sites may represent a novel .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.A. Christopoulos, L.T. May, V.A. Avlani and P.M. Sexton (2004) G-protein-coupled receptor allosterism:the promise and the problem(s). "Biochemical Society Transactions" Volume 32, part 5 ] Therefore greater GPCR selectivity may be obtained by targeting allosteric sites.This is particularly useful for GPCRs where selective orthosteric therapy has been difficult because of sequence conservation of the orthosteric site across receptor subtypes. L.T. May , K. Leach, P.M. Sexton, and A. Christopoulos. (2007). Allosteric Modulation of GProtein–Coupled Receptors "Annu. Rev. Pharmacol. Toxicol." 47:1–51 ] 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. 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. 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.
Homotropic allosteric interaction
A "homotropic allosteric interaction" is one in which the activity of an
allosteric proteinis regulated by its substrate. Homotropic modulators tend to be allosteric activators; that is, they typically up-regulate the activity of the protein. They can do so by inducing the comfomational change of the multi-subunit allosteric protein from the inactive state (Tense state) to the active state (Relaxed state). Homotropic effects are in contrast to heterotropic effects in which the allosteric modulator is something other than the protein's substrate.
Heterotropic allosteric modulator
A "heterotropic allosteric interaction" is one in which the activity of an
allosteric proteinis regulated by a molecule other than the protein's substrate. Heterotropic effects are in contrast to homotropic effects in which the allosteric proteinis regulated by its substrate.
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