Is there a common allosteric binding site for G-protein coupled receptors?

Abstract

Targeting the allosteric sites on G-protein coupled receptors (GPCRs) for drug discovery is attracting increased interest. Given a GPCR target, identifying the allosteric binding sites in it remains a challenge. Previous works from our and other labs suggest the intracellular region below the middle of the transmembrane (TM) domain that spatially overlaps with the G-protein binding site could contain a common allosteric site for all GPCRs. We performed several bioinformatics analyses on this site for more than 100 representative human GPCR structures. Results of the studies confirmed that the proposed region contains an allosteric site that is druggable for 89% of the GPCRs and is not 100% identical between a GPCR and its most similar homolog for 94% of the GPCRs. The physico-chemical properties and amino acid composition of this site vary among and within GPCR classes. Since this proposed region occupies the space existing in all GPCRs of known structure, it could represent a common host of an allosteric site for all GPCRs that can be targeted for structure-based allosteric drug design.

Keywords: Allosteric binding site; Conservation analysis; Druggability analysis; GPCR.