Allosteric modulator

In biochemistry and pharmacology, an allosteric modulator (allo- from the Greek meaning "other") is a substance which indirectly influences (modulates) the effects of an agonist or inverse agonist at a target protein, for example a receptor. Allosteric modulators bind to a site distinct from that of the orthosteric agonist binding site. Usually they induce a conformational change within the protein structure. A positive allosteric modulator (PAM) or allosteric enhancer induces an amplification of the orthosteric agonist's effect, either by enhancing the binding affinity or the functional efficacy of the orthosteric agonist for the target protein.^[1] A negative modulator (NAM) reduces the effects of the orthosteric ligand, but is inactive in the absence of the orthosteric ligand. Substances that occupy the allosteric binding site and are functionally neutral are called silent allosteric modulators (SAMs). Classic benzodiazepines are well-known PAMs.

The modulatory activity can be first-order or second-order (or both). Second-order modulators alter the modulatory activity of first-order modulators. (−)‐Epigallocatechin‐3‐gallate is one such example of a second-order modulator at GABA_A receptors.^[2]

Allosteric agonists are to be distinguished from pure allosteric modulators. They are defined as ligands able to directly activate a receptor by binding to a receptor site distinct from the primary (orthosteric) site, the allosteric site. They are able to bind the target protein and exert their effect in the absence of an orthosteric ligand, whereas the presence of an orthosteric ligand is typically required to observe the indirect effects of pure allosteric modulators.

Ago-allosteric modulators are both allosteric agonists and allosteric modulators. An ago-allosteric modulator acts as an agonist and an enhancer for endogenous agonists in increasing agonist potency (the dose range over which a response is produced) and providing "superagonism". Superagonism results when the efficacy is greater than 100 percent. Ago-allosteric modulators can be neutral, negative, or positive. Neutral ago-allosteric modulators increase efficacy, but have no effect on potency. A negative ago-allosteric modulator has a negative effect on the potency but a positive effect on the efficacy of an agonist. A positive ago-allosteric modulator increases both efficacy and potency.

See also

• Allosteric regulation

Notes

1. May, Lauren T.; Leach, Katie; Sexton, Patrick M.; Christopoulos, Arthur (2007). "Allosteric Modulation of G Protein–Coupled Receptors". Annual Review of Pharmacology and Toxicology 47 (1): 1–51. doi:10.1146/annurev.pharmtox.47.120505.105159. PMID 17009927. Retrieved 2015-04-18.
2. Campbell EL, Chebib M, Johnston GAR (2004): "The dietary flavonoids apigenin and (−)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABAA receptors", Biochemical Pharmacology, Vol. 68, 1631

References

• J. Monod, J. Wyman, J.P. Changeux (1965). "On the nature of allosteric transitions: A plausible model". Journal of Molecular Biology 12 (1): 88–118. doi:10.1016/S0022-2836(65)80285-6. PMID 14343300.
• T.W. Schwartz, B. Holst (2006). "Ago-allosteric modulation and other types of allostery in dimeric 7TM receptors". Journal of Receptors and Signal Transduction Research 26 (1): 88–118.
• Schwartz, Thue W., and Birgitte Holst. (2007). "Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?". Trends in Pharmacological Sciences 28 (8): 366–373. doi:10.1016/j.tips.2007.06.008.