Regulation of G protein-coupled receptors by allosteric ligands

Abstract

Topographically distinct, druggable, allosteric sites may be present on all G protein-coupled receptors (GPCRs). As such, targeting these sites with synthetic small molecules offers an attractive approach to develop receptor-subtype selective chemical leads for the development of novel therapies. A crucial part of drug development is to understand the acute and chronic effects of such allosteric modulators at their corresponding GPCR target. Key regulatory processes including cell-surface delivery, endocytosis, recycling, and down-regulation tightly control the number of receptors at the surface of the cell. As many GPCR therapeutics will be administered chronically, understanding how such ligands modulate these regulatory pathways forms an essential part of the characterization of novel GPCR ligands. This is true for both orthosteric and allosteric ligands. In this Review, we summarize our current understanding of GPCR regulatory processes with a particular focus on the effects and implications of allosteric targeting of GPCRs.

Figure 1

Schematic representation of GPCR regulation by β-arrestin mediated endocytosis. Phosphorylation of the activated receptor by GRKs triggers the recruitment of β-arrestin and the scaffolding of the endocytic machinery that results in receptor internalization. Once in endosomes, GPCRs can be dephosphorylated and recycled to the plasma membrane or, alternatively, be targeted for lysosomal degradation via multivesicular bodies (MVB).

Figure 2

GPCR drug discovery has predominantly focused upon targeting the orthosteric site where the endogenous agonist binds. Allosteric modulators bind to a site on a GPCR that is topographically distinct from this orthosteric binding site. Allosteric modulators will bind to a receptor selecting a distinct receptor conformation but will still allow orthosteric ligands to bind. As such, allosteric ligands can modulate both orthosteric ligand affinity and efficacy. Of particular note, allosteric ligands can also possess their own intrinsic efficacy.

Figure 3

Both orthosteric and allosteric GPCR ligands acting at the same receptor can engage acute signaling and regulatory pathways by interacting with distinct effector proteins (Eff. A-C) and regulatory proteins such as β-arrestin (β-arr). Both orthosteric and allosteric ligands may select different subsets of these signaling and regulatory pathways by stabilizing distinct receptor conformations, a phenomenon termed functional selectivity or stimulus bias. The subset of these pathways and processes engaged by a ligand–receptor complex will underlie the physiological effect of the ligand.