Common evolutionary binding mode of rhodopsin-like GPCRs: Insights from structural bioinformatics

Abstract

G-protein Coupled Receptors (GPCRs) form the largest membrane protein superfamily in vertebrates. Advances in crystallization techniques so far resulted in the resolution of 44 unique receptors available for the GPCRs researcher’s community, 37 of which belong to rhodopsin-like GPCRs class. We performed here the first systematic analysis of GPCRs binding cavities based on the available pool of rhodopsin-like solved structures. We pinpointed ten positions shared between all the solved receptors, namely 3.32, 3.33, 3,36, 6.48, 6.51, 6.52, 6.55, 7.35, 7.39 and 7.43, as interacting with ligands. We analyzed the conservation of amino acids present in these positions and clustered GPCRs accordingly to the physicochemical properties of binding cavities’ residues. Clustering supplied new interesting insights into the common binding mode of these receptors. In particular, the 3.32 position turned out to have an important role in ligand charge detection. Finally, we demonstrated that residues in these ten positions have co-evolved together, sharing a common evolutionary history.