In biochemistry and pharmacology, an allosteric modulator 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), which is also called an allosteric enhancer, induces an amplification of the agonists effect. A negative modulator (NAM) is an attenuation of the effects of the orthosteric ligand without triggering a functional activity on its own in the absence of the orthosteric ligand. Substances that occupy the allosteric binding site and behave functionally neutral are called silent allosteric modulators (SAMs). Classic benzodiazepines are well-known PAMs.
From modulators the allosteric agonists are to be distinguished. They are able to directly activate a receptor via an allosteric binding site in the absence of an orthosteric ligand.
An ago-allosteric modulator acts as an agonist and an enhancer for endogenous agonists in increasing agonist potency (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 affect 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.
- J. Monod, J. Wyman, J.P. Changeux (May 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 (January 2006). "Ago-allosteric modulation and other types of allostery in dimeric 7TM receptors". J Recept Signal Transduct Res. 2006 26 (1): 88–118.
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