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

ABSTRACT: 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 ?-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 ?₂ adrenergic receptor (?₂AR; 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 ?₂AR. 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.

SUBMITTER: Hilger D 

PROVIDER: S-EPMC7954662 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature