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
  • 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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