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TitleStructure and dynamics determine G protein coupling specificity at a class A GPCR.
Journal, issue, pagesSci Adv, Vol. 11, Issue 12, Page eadq3971, Year 2025
Publish dateMar 21, 2025
AuthorsMarina 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 AbstractG 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 linksSci Adv / PubMed:40106559 / PubMed Central
MethodsEM (single particle)
Resolution2.9 Å
Structure data

EMDB-44925, PDB-9buy:
Structure of the LM189-Bound beta2AR-Gi Complex
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

PDB-1asm:
CRYSTAL STRUCTURES OF ESCHERICHIA COLI ASPARTATE AMINOTRANSFERASE IN TWO CONFORMATIONS: COMPARISON OF AN UNLIGANDED OPEN AND TWO LIGANDED CLOSED FORMS

ChemComp-KBY:
N-[(3R)-4-(4-tert-butylphenyl)-3-({2-[(4-methoxyphenyl)sulfanyl]-5-[methyl(propan-2-yl)sulfamoyl]benzene-1-carbonyl}amino)butanoyl]glycine

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / SIGNALING PROTEIN-IMMUNE SYSTEM complex

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