Faculty Collaboration Database

Structure and dynamics determine G protein coupling specificity at a class A GPCR. bioRxiv 2025 Jan 31

Date

04/08/2024

Pubmed ID

38586060

Pubmed Central ID

PMC10996611

DOI

10.1101/2024.03.28.587240

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 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.

Author List

Casiraghi M, Wang H, Brennan P, Habrian C, Hubner H, Schmidt MF, Maul L, Pani B, Bahriz SM, Xu B, White E, Sunahara RK, Xiang YK, Lefkowitz RJ, Isacoff EY, Nucci N, Gmeiner P, Lerch M, Kobilka BK

Author

Michael Lerch PhD Associate Professor in the Biophysics department at Medical College of Wisconsin