G-protein coupled receptors (GPCRs) mediate signal transduction across membranes and are the number one target for drugs currently available in the market. In recent years, targeting the allosteric sites on GPCRs for the development of drugs to treat various diseases is attracting increased interest. Given a GPCR target, identifying the allosteric binding sites in it represents the first important step for structure-based allosteric drug design. This step, however, remains a challenge. Among various allosteric sites reported, of particular interest is the intracellular allosteric site below the middle of the TM domain that spatially overlaps with the G-protein binding site. Previous works from our and other labs suggest this region could be a common allosteric site for all GPCRs. In this work, we performed druggability and conservation analyses on this site for more than 100 human GPCRs whose structures are available. Results of the studies confirmed that the proposed site is druggable for most of the GPCRs and few of this site is 100% identical between a GPCR and its most similar homolog. These results suggest the proposed site can be targeted for the design of selective ligands. Since this proposed allosteric site occupies the space existing in all GPCRs of known structure, it could be a common allosteric site for all GPCRs. Thus, the work reported here is of practical use to the structure-based drug discovery targeting GPCRs.

Is there a common allosteric site for regulation of GPCRs?

ACS Spring 2022

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