Structure and dynamics determine G protein coupling specificity at a class A GPCR
Marina Casiraghi, Haoqing Wang, Patrick J. Brennan, Chris Habrian, Harald Hübner, Maximilian F. Schmidt, Luis Maul, Biswaranjan Pani, Sherif Bahriz, Bing 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
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 β 2 -adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase. By developing a Gαi-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 Gαs and Gαi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways.