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| Title | Structure and dynamics determine G protein coupling specificity at a class A GPCR. |
|---|---|
| Journal, issue, pages | Sci Adv, Vol. 11, Issue 12, Page eadq3971, Year 2025 |
| Publish date | Mar 21, 2025 |
Authors | Marina Casiraghi / Haoqing Wang / Patrick C Brennan / Chris Habrian / Harald Hübner / Maximilian F Schmidt / Luis Maul / Biswaranjan Pani / Sherif M F M Bahriz / Bing Xu / Nico Staffen / Tufa E Assafa / Bohan Chen / Elizabeth White / Roger K Sunahara / Asuka Inoue / Yang K Xiang / Robert J Lefkowitz / Ehud Y Isacoff / Nathaniel Nucci / Peter Gmeiner / Michael T Lerch / Brian K Kobilka / ![]() |
| PubMed 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 ...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 β-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. |
External links | Sci Adv / PubMed:40106559 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.9 Å |
| Structure data | EMDB-44925, PDB-9buy: |
| Chemicals | ![]() ChemComp-CLR: ![]() PDB-1asm: ![]() ChemComp-KBY: |
| Source |
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Keywords | SIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / SIGNALING PROTEIN-IMMUNE SYSTEM complex |
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