Novel Allosteric Modulators of G Protein-coupled Receptors

Abstract

G protein-coupled receptors (GPCRs) are allosteric proteins, because their signal transduction relies on interactions between topographically distinct, yet conformationally linked, domains. Much of the focus on GPCR allostery in the new millennium, however, has been on modes of targeting GPCR allosteric sites with chemical probes due to the potential for novel therapeutics. It is now apparent that some GPCRs possess more than one targetable allosteric site, in addition to a growing list of putative endogenous modulators. Advances in structural biology are also shedding new insights into mechanisms of allostery, although the complexities of candidate allosteric drugs necessitate rigorous biological characterization.

Keywords: G protein; G protein-coupled receptor (GPCR); allosteric regulation; biased agonism; bitopic ligand; chemical biology; drug discovery; structural biology.

FIGURE 1.

Potential allosteric ligand-binding regions on GPCRs; some representative allosteric modulators recognizing each region are also listed. RAMP, receptor activity-modifying protein; MRAP, melanocortin receptor accessory protein; Cmpd, compound; AZ, AstraZeneca; Fz4, frizzled4 receptor; CaSR, calcium-sensing receptor; PCEP, 3-amino-3-carboxypropyl-2′-carboxyethyl phosphinic acid.

FIGURE 2.

Timeline of representative GPCR crystal structures, 2000–2015. N/OFQ, nociception/orphanin FQ receptor; SMO, Smoothened receptor; OR, opioid receptor; H₁, histamine H₁ receptor; S1P1, sphingosine-1-phosphate 1 receptor.