Overview of Receptor Allosterism

Abstract

In addition to the orthosteric site, which recognizes endogenous ligands, most G protein-coupled receptors (GPCRs) possess topographically distinct allosteric sites that can be recognized by small molecules and accessory cellular proteins. Ligand binding to allosteric sites promotes a conformational change in the GPCR that can alter orthosteric ligand affinity and/or efficacy. Moreover, there has been an increase in recent years in the identification of allosteric agonists that can directly activate the receptor in the absence of orthosteric ligand. Allosteric sites are attractive therapeutic targets because they can be exploited to achieve modes of selectivity and signaling that are not attainable by orthosteric means. However, an important challenge in this field remains the quantification of the myriad of possible allosteric effects on binding and signaling events. This unit provides an overview on GPCR allosterism and the different pharmacological approaches to understanding allosteric behaviors.

Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders

“…These equations take the interactions among the receptor, orthosteric ligands, allosteric ligands and effector proteins into account and provide a computational approach to define the magnitude and direction of an allosteric effect, using one or more cooperativity factors 18,22 . More recently, an operational model of allosterism that describes the allosteric modulation of both affinity and efficacy was introduced; this model also incorporates the ability of a compound to induce allosteric agonism 23–25 . Briefly, in the operational model, modulation of binding affinity is governed by a cooperativity factor, which is denoted as α, and allosteric modulation of efficacy is incorporated by the introduction of the parameter β.…”

Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities

“…A composite cooperativity factor logαβ defines the combined modulation effects on affinity and efficacy of orthosteric ligands. The following equation describes the operational model of allosterism (Gregory et al, 2010):] $$E=\frac{E_m{false({\tau }_{A}false[Afalse]false(K_B+\alpha \beta false[Bfalse]false)+{\tau }_{B}false[Bfalse]K_{A}false)}^n}{{false(false[Afalse]K_B+K_A{K}_B+K_{A}false[Bfalse]+\alpha false[Afalse]false[Bfalse]false)}^n+{false({\tau }_{A}false[Afalse]false(K_B+\alpha \beta false[Bfalse]false)+{\tau }_{B}false[Bfalse]K_{A}false)}^n}$$ where E and E m represents the effect and the maximum possible effect respectively and n represents the slope factor that governs the shape of the stimulus-response function. If the allosteric ligand has no intrinsic efficacy, the equation simplifies to the following (May et al, 2007; Gregory et al, 2010): $$E=\frac{E_m{\mathrm{\tau }}^n{false[Afalse]}^n{\left(1+\frac{\text{αβ}[B]}{K_B}\right)}^n}{{\left[[A]\left(1+\frac{\alpha [B]}{K_B}\right)+K_A\left(1+\frac{[B]}{K_B}\right)\right]}^n+{\mathrm{\tau }}^n{false(Afalse)}^n{\left(1+\frac{\alpha \beta [B]}{K_B}\right)}^n}$$…”

Approaches for Probing Allosteric Interactions at 7 Transmembrane Spanning Receptors

“…For quantitative analysis of allosteric modulator effect on orthosteric radioligand binding, the ATCM, which accounts for both allosteric and orthosteric binding and the effect of the former on the latter, may be applied. 144,145 Fitting the data to this model will allow determination of the affinity of the allosteric modulator and its cooperativity factor, α , for the radioligand, which is a measure of the degree that an allosteric modulator affects the binding of the orthosteric ligand (0< α <1 for NAMs; α >1 for PAMs). 4 In the case where the modulator does not alter the affinity ( α =1), no change in binding will be observed.…”