Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

Nature. 2017 Jun 8;546(7657):248-253. doi: 10.1038/nature22394. Epub 2017 May 24.

Abstract

Glucagon-like peptide 1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR) that signals primarily through the stimulatory G protein Gs. Class B GPCRs are important therapeutic targets; however, our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we report the cryo-electron microscopy structure of the peptide-activated GLP-1R-Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and the transmembrane core of the receptor, and further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5-helix of the Ras-like domain of Gs. These results provide a structural framework for understanding class B GPCR activation through hormone binding.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cryoelectron Microscopy*
  • GTP-Binding Protein alpha Subunits, Gs / chemistry*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • GTP-Binding Protein alpha Subunits, Gs / ultrastructure*
  • Glucagon-Like Peptide 1 / chemistry*
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor / chemistry*
  • Glucagon-Like Peptide-1 Receptor / classification
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Glucagon-Like Peptide-1 Receptor / ultrastructure*
  • Models, Molecular
  • Protein Domains
  • Rabbits

Substances

  • Glucagon-Like Peptide-1 Receptor
  • Glucagon-Like Peptide 1
  • GTP-Binding Protein alpha Subunits, Gs