Structural insights into differences in G protein activation by family A and family B GPCRs

Hilger, Daniel; Kumar, Kaavya Krishna; Hu, Hongli; Pedersen, Mie Fabricius; O’Brien, Evan S.; Giehm, Lise; Jennings, Christine; Eskici, Gözde; Inoue, Asuka; Lerch, Michael; Mathiesen, Jesper Mosolff; Skiniotis, Georgios; Kobilka, Brian K.

doi:10.1126/science.aba3373

Structural insights into differences in G protein activation by family A and family B GPCRs

Journal Article · Thu Jul 30 00:00:00 EDT 2020 · Science

DOI:https://doi.org/10.1126/science.aba3373· OSTI ID:1656572

^[1]; ^[2]; ^[3]; Pedersen, Mie Fabricius ^[4]; ^[2]; ^[4]; ^[5]; ^[2]; Inoue, Asuka ^[6]; ^[5]; ^[4]; ^[7]; ^[2]

Stanford Univ., CA (United States); Phillips Univ. Marburg (Germany)
Stanford Univ., CA (United States)
Stanford Univ., CA (United States); Chinese Univ. of Hong Kong, Shenzhen, GD (China). Kobilka Inst. of Innovative Drug Discovery
Zealand Pharma A/S, Søborg (Denmark)
Univ. of Wisconsin, Milwaukee, WI (United States)
Tohoku Univ., Sendai (Japan)
Stanford Univ., CA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)

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_s 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 β₂ adrenergic receptor (β₂AR; family A). We determined the structure of the GCGR-G_s 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 β₂AR. 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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); KAKENHI; Japan Society for the Promotion of Science (JSPS); Japan Agency for Medical Research and Development (AMED); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1656572

Journal Information:: Science, Journal Name: Science Journal Issue: 6503 Vol. 369; ISSN 0036-8075

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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