Allosteric binding sites at the receptor-lipid bilayer interface: novel targets for GPCR drug discovery.

As a superfamily of membrane receptors, G-protein-coupled receptors (GPCRs) have significant roles in human physiological processes, including cell proliferation, metabolism, and neuromodulation. GPCRs are vital targets of therapeutic drugs, and their allosteric regulation represents a novel direction for drug discovery. Given the numerous breakthroughs in structural biology, diverse allosteric sites on GPCRs have been identified within the extracellular and intracellular loops, and the seven core transmembrane helices. However, a unique type of allosteric site has also been discovered at the interface of the receptor-lipid bilayer, similar to the β2-adrenergic receptor. Here, we review recent identifications of these allosteric sites and the detailed modulator-target interactions within the interface for each modulator to highlight the role of lipids in GPCR allosteric drug discovery.