2. Academic Validation
  3. Structure and dynamics determine G protein coupling specificity at a class A GPCR

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

  • Sci Adv. 2025 Mar 21;11(12):eadq3971. doi: 10.1126/sciadv.adq3971.
Marina Casiraghi 1,  Haoqing Wang 1,  Patrick C Brennan 2,  Chris Habrian 1,  Harald Hübner 3 4,  Maximilian F Schmidt 3 4,  Luis Maul 3 4,  Biswaranjan Pani 5,  Sherif M F M Bahriz 6,  Bing Xu 6 7,  Nico Staffen 3 4,  Tufa E Assafa 8,  Bohan Chen 9,  Elizabeth White 1,  Roger K Sunahara 9,  Asuka Inoue 10 11,  Yang K Xiang 6 7,  Robert J Lefkowitz 5 12 13,  Ehud Y Isacoff 14 15,  Nathaniel Nucci 16,  Peter Gmeiner 3 4,  Michael T Lerch 2,  Brian K Kobilka 1
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2 Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 3 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • 4 FAU NeW, Erlangen, Germany.
  • 5 Department of Medicine, Duke University Medical Center, Durham, NC, USA.
  • 6 Department of Pharmacology, University of California, Davis, Davis, CA, USA.
  • 7 VA Northern California Health Care System, Mather, CA, USA.
  • 8 Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, USA.
  • 9 Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA, USA.
  • 10 Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
  • 11 Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
  • 12 Department of Biochemistry, Duke University Medical Center, Durham, NC, USA.
  • 13 HHMI, Duke University Medical Center, Durham, NC, USA.
  • 14 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 15 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
  • 16 Department of Physics and Astronomy and Department of Biological and Biomedical Biosciences, Rowan University, Glassboro, NJ, USA.
PMID: 40106559 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.

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