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TitleStructural insights into differences in G protein activation by family A and family B GPCRs.
Journal, issue, pagesScience, Vol. 369, Issue 6503, Year 2020
Publish dateJul 31, 2020
AuthorsDaniel Hilger / Kaavya Krishna Kumar / Hongli Hu / Mie Fabricius Pedersen / Evan S O'Brien / Lise Giehm / Christine Jennings / Gözde Eskici / Asuka Inoue / Michael Lerch / Jesper Mosolff Mathiesen / Georgios Skiniotis / Brian K Kobilka /
PubMed AbstractFamily B heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play important roles in carbohydrate metabolism. Recent structures of family B GPCR-G protein ...Family B heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play important roles in carbohydrate metabolism. Recent structures of family B GPCR-G protein complexes reveal a disruption in the α-helix of transmembrane segment 6 (TM6) not observed in family A GPCRs. To investigate the functional impact of this structural difference, we compared the structure and function of the glucagon receptor (GCGR; family B) with the β adrenergic receptor (βAR; family A). We determined the structure of the GCGR-G complex by means of cryo-electron microscopy at 3.1-angstrom resolution. This structure shows the distinct break in TM6. Guanosine triphosphate (GTP) turnover, guanosine diphosphate release, GTP binding, and G protein dissociation studies revealed much slower rates for G protein activation by the GCGR compared with the βAR. Fluorescence and double electron-electron resonance studies suggest that this difference is due to the inability of agonist alone to induce a detectable outward movement of the cytoplasmic end of TM6.
External linksScience / PubMed:32732395 / PubMed Central
MethodsEM (single particle)
Resolution3.1 Å
Structure data

EMDB-21866, PDB-6wpw:
GCGR-Gs signaling complex bound to a designed glucagon derivative
Method: EM (single particle) / Resolution: 3.1 Å

Source
  • homo sapiens (human)
  • lama glama (llama)
  • synthetic construct (others)
KeywordsSIGNALING PROTEIN/HORMONE/IMMUNE SYSTEM / GPCR / G protein / glucagon / signaling / complex / SIGNALING PROTEIN-HORMONE-IMMUNE SYSTEM complex

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