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

Casiraghi M, Wang H, Brennan PC, Habrian C, Hübner H, Schmidt M, Maul L, Pani B, Bahriz SM, Xu B, Staffen N, Assafa TE, Chen B, White E, Sunahara RK, Inoue A, Xiang YK, Lefkowitz RJ, Isacoff EY, Nucci N, Gmeiner P, Lerch MT, Kobilka BK (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 11

Article Number: eadq3971

Journal Issue: 12

DOI: 10.1126/sciadv.adq3971

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 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.

Authors with CRIS profile

Involved external institutions

University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Tohoku University Japan (JP) Stanford University United States (USA) (US) Medical College of Wisconsin (MCW) United States (USA) (US) University of California, Davis (UC Davis, UCD) United States (USA) (US) Duke University Medical Center United States (USA) (US) University of California, Santa Cruz (UC Santa Cruz, UCSC) United States (USA) (US) University of California, Berkeley (UC Berkeley) United States (USA) (US) Rowan University United States (USA) (US)

How to cite

APA:

Casiraghi, M., Wang, H., Brennan, P.C., Habrian, C., Hübner, H., Schmidt, M.,... Kobilka, B.K. (2025). Structure and dynamics determine G protein coupling specificity at a class A GPCR. Science Advances, 11(12). https://doi.org/10.1126/sciadv.adq3971

MLA:

Casiraghi, Marina, et al. "Structure and dynamics determine G protein coupling specificity at a class A GPCR." Science Advances 11.12 (2025).

BibTeX: Download