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

Science. 2020 Jul 31;369(6503):eaba3373. doi: 10.1126/science.aba3373.

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-Gs 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-Gs 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cryoelectron Microscopy
  • Enzyme Activation
  • GTP-Binding Protein alpha Subunits, Gs / chemistry*
  • Humans
  • Protein Structure, Secondary
  • Receptors, Adrenergic, beta-2 / chemistry*
  • Receptors, Glucagon / chemistry*

Substances

  • Receptors, Adrenergic, beta-2
  • Receptors, Glucagon
  • GTP-Binding Protein alpha Subunits, Gs