Allosteric Binding Site

An allosteric site is a specific region on a protein, such as a receptor or enzyme, that is topographically distinct from the orthosteric or active site where endogenous ligands or substrates typically bind (Nature Reviews Drug Discovery, 2002). Binding of a molecule to this site triggers a conformational change that propagates through the protein structure, ultimately altering the functional properties of the orthosteric site (Annual Review of Pharmacology and Toxicology, 2013). This mechanism, known as allosteric modulation, can either enhance (positive modulation) or diminish (negative modulation) the protein's activity or its affinity for its natural ligand (Nature Reviews Drug Discovery, 2009). In drug discovery, targeting allosteric sites is highly valued because these sites are often less conserved than active sites, allowing for greater drug selectivity between closely related protein subtypes (Cell, 2013). Furthermore, allosteric modulators can maintain the physiological timing of signaling because they only exert their effect when the endogenous ligand is present (Annual Review of Pharmacology and Toxicology, 2007). This approach is utilized across various therapeutic areas, including neurology, where benzodiazepines modulate GABA-A receptors, and oncology, where allosteric inhibitors are developed for kinases like BCR-ABL (Nature, 2017).

Other names

Allosteric pocketExositeSecondary binding siteNon-orthosteric siteRegulatory site

Allosteric modulation (PAM, NAM, or SAM) which involves binding to a site distinct from the orthosteric site to induce conformational changes that alter the protein's functional response to its primary ligand or substrate (Nature Reviews Drug Discovery, 2002).