Structure and dynamics determine G protein coupling specificity at a class A GPCR. Sci Adv 2025 Mar 21;11(12):eadq3971
Date
03/19/2025Pubmed ID
40106559Pubmed Central ID
PMC12101717DOI
10.1126/sciadv.adq3971Scopus ID
2-s2.0-105000968573 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
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.
Author List
Casiraghi M, Wang H, Brennan PC, Habrian C, Hübner H, Schmidt MF, Maul L, Pani B, Bahriz SMFM, 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 BKAuthor
Michael Lerch PhD Associate Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
GTP-Binding Protein alpha Subunits, GsGTP-Binding Proteins
HEK293 Cells
Humans
Ligands
Models, Molecular
Protein Binding
Protein Conformation
Receptors, Adrenergic, beta-2
Receptors, G-Protein-Coupled
Signal Transduction
