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In biochemistry, allosteric regulation is the regulation of an enzyme or other 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, "solid (object)," in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site. Allosteric regulations are natural example of control loops, such as feedback from downstream products or feedforward from upstream substrates.

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.

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).

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, in essence, 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 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.


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]

Another example is strychnine, a convulsant poison, which acts 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.

Types of allosteric regulation: homotropic and heterotropic[]

Many allosteric enzymes 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 change in 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, Librium and Ativan, for example, “potentiate” 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 that allosterically modulate their drug targets include Cinacalcet and Maraviroc.

Allosteric sites as drug targets[]

Allosteric sites may represent a novel drug target. There is 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]

See also[]

  • Cooperative binding
  • Enzyme kinetics
  • Protein dynamics


  1. J. Monod, J. Wyman, J.P. Changeux. (1965). On the nature of allosteric transitions:A plausible model. J. Mol. Biol., May;12:88-118.
  2. 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
  3. 3.0 3.1 3.2 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
  4. 4.0 4.1 4.2 L.T. May , K. Leach, P.M. Sexton, and A. Christopoulos. (2007). Allosteric Modulation of G Protein–Coupled Receptors Annu. Rev. Pharmacol. Toxicol. 47:1–51

External links[]

  • Instant insight introducing a classification system for protein allostery mechanisms from the Royal Society of Chemistry
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