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

作者：Marina Casiraghi, Haoqing Wang, Patrick J. Brennan, Chris Habrian, Harald Hübner, Maximilian F. Schmidt, Luis Maul, Biswaranjan Pani, Sherif M. Bahriz, Bing Xu, Elizabeth White, Roger K. Sunahara, Yang K. Xiang, Robert J. Lefkowitz, Ehud Y. Isacoff, Nathaniel V. Nucci, Peter Gmeiner, Michael T. Lerch, Brian K. Kobilka · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.03.28.587240 · 被引用次数：7 · 研究领域：Receptor Mechanisms and Signaling、Protein Kinase Regulation and GTPase Signaling、Neuropeptides and Animal Physiology

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 β2-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 new 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.