Conformational states of the full-length glucagon receptor

Nat Commun. 2015 Jul 31:6:7859. doi: 10.1038/ncomms8859.


Class B G protein-coupled receptors are composed of an extracellular domain (ECD) and a seven-transmembrane (7TM) domain, and their signalling is regulated by peptide hormones. Using a hybrid structural biology approach together with the ECD and 7TM domain crystal structures of the glucagon receptor (GCGR), we examine the relationship between full-length receptor conformation and peptide ligand binding. Molecular dynamics (MD) and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. The electron microscopy (EM) map of the full-length GCGR shows how a monoclonal antibody stabilizes the ECD and 7TM domain in an elongated conformation. Hydrogen/deuterium exchange (HDX) studies and MD simulations indicate that an open conformation is also stabilized by peptide ligand binding. The combined studies reveal the open/closed states of GCGR and suggest that glucagon binds to GCGR by a conformational selection mechanism.

Publication types

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

MeSH terms

  • Animals
  • Chromatography, Liquid
  • Deuterium Exchange Measurement
  • Disulfides / chemistry
  • Disulfides / metabolism
  • Glucagon / metabolism*
  • Humans
  • Ligands
  • Microscopy, Electron
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Glucagon / chemistry
  • Receptors, Glucagon / metabolism*
  • Receptors, Glucagon / ultrastructure
  • Sf9 Cells
  • Tandem Mass Spectrometry


  • Disulfides
  • Ligands
  • Receptors, Glucagon
  • Glucagon