Structural basis of Gs and Gi recognition by the human glucagon receptor

Science. 2020 Mar 20;367(6484):1346-1352. doi: 10.1126/science.aaz5346.

Abstract

Class B G protein-coupled receptors, an important class of therapeutic targets, signal mainly through the Gs class of heterotrimeric G proteins, although they do display some promiscuity in G protein binding. Using cryo-electron microscopy, we determined the structures of the human glucagon receptor (GCGR) bound to glucagon and distinct classes of heterotrimeric G proteins, Gs or Gi1 These two structures adopt a similar open binding cavity to accommodate Gs and Gi1 The Gs binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect Gi more than Gs binding. Conformational differences in the receptor intracellular loops were found to be key selectivity determinants. These distinctions in transducer engagement were supported by mutagenesis and functional studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cryoelectron Microscopy
  • GTP-Binding Protein alpha Subunits, Gi-Go / chemistry*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / ultrastructure
  • GTP-Binding Protein alpha Subunits, Gs / chemistry*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • GTP-Binding Protein alpha Subunits, Gs / ultrastructure
  • Glucagon / chemistry*
  • Glucagon / metabolism
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Protein Conformation, alpha-Helical
  • Receptors, Glucagon / chemistry*
  • Receptors, Glucagon / metabolism
  • Receptors, Glucagon / ultrastructure
  • Signal Transduction

Substances

  • Receptors, Glucagon
  • Glucagon
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gs