Structure and dynamics determine G protein coupling specificity at a class A GPCR

Marina Casiraghi; Haoqing Wang; Patrick C. Brennan; Chris H. Habrian; Harald Hübner; Maximilian F. Schmidt; Luis Maul; Biswaranjan Pani; Sherif M. F. M. Bahriz; Bing Ying Xu; Nico Staffen; Tufa E. Assafa; Bohan Chen; Elizabeth White; Roger K. Sunahara; Asuka Inoue; Yang K. Xiang; Robert J. Lefkowitz; Ehud Y. Isacoff; Nathaniel V. Nucci; Peter Gmeiner; Michael T. Lerch; Brian K. Kobilka

doi:10.1126/sciadv.adq3971

Molecular BiologyScience AdvancesMar 19, 2025

Peer-reviewed journal article

Structure and dynamics determine G protein coupling specificity at a class A GPCR

Marina Casiraghi iD, Haoqing Wang iD, Patrick C. Brennan iD, Chris H. Habrian, Harald Hübner iD, Maximilian F. Schmidt iD, Luis Maul iD, Biswaranjan Pani iD, Sherif M. F. M. Bahriz iD, Bing Ying Xu iD, Nico Staffen, Tufa E. Assafa iD, Bohan Chen iD, Elizabeth White, Roger K. Sunahara iD, Asuka Inoue iD, Yang K. Xiang iD, Robert J. Lefkowitz iD, Ehud Y. Isacoff iD, Nathaniel V. Nucci iD, Peter Gmeiner iD, Michael T. Lerch iD, Brian K. Kobilka iD

Abstract

G protein coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The {beta}2-adrenergic receptor is an example of GPCR with high selectivity for Gs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gi family of G proteins inhibiting adenylyl cyclase. By developing a Gi-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Gs and Gi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways.

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