Received for publication August 24, 2006.
Revised October 26, 2006.
Accepted for publication December 20, 2006.

The Highly Conserved DRY Motif of Class A GPCRs: Beyond the Ground State

Abstract

Despite extensive study of heptahelical G protein-coupled receptors (GPCRs), the precise mechanism of G protein activation is unknown. The role of one highly conserved stretch of residues, the amino acids Glu/Asp-Arg-Tyr, (i.e. the E/DRY motif) has received considerable attention with respect to regulating GPCR conformational states. In the consensus view, Glu/Asp maintains the receptor in its ground state, since mutations frequently induce constitutive activity (CA). This hypothesis has been confirmed by the rhodopsin ground-state crystal structure and by computational modeling approaches. However, some class A GPCRs are resistant to CA, suggesting alternative roles for the Glu/Asp residue and the E/DRY motif. Here we propose two different subgroups of receptors within class A GPCRs that make different use of the E/DRY motif, independent of the G protein type (G_s, G_i or G_q) to which the receptor couples. In P1-type receptors, non-conservative mutations of the Glu/Asp-Arg residues, besides inducing CA, increase affinity for agonist binding, retain G protein coupling, and retain an agonist-induced response. In contrast, in P2-type receptors, the E/DRY motif is more directly involved in governing receptor conformation and G protein coupling/recognition. Hence, mutations of the Glu/Asp residues do not induce CA. Conversely, non-conservative mutations of the Arg of the E/DRY motif always impair agonist-induced receptor responses and, generally, reduce agonist binding affinity. Thus, it is essential to look beyond the rhodopsin ground state model of conformational activation to clarify the role of this highly conserved triplet in GPCR activation and function.

Key words: G protein regulation, Desensitization/uncoupling, Structure-activity relationships and modeling, Prediction of structure-function/proteomics

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