Inhibitory mechanism of an allosteric antibody targeting the glucagon receptor

J Biol Chem. 2013 Dec 13;288(50):36168-78. doi: 10.1074/jbc.M113.496984. Epub 2013 Nov 4.


Elevated glucagon levels and increased hepatic glucagon receptor (GCGR) signaling contribute to hyperglycemia in type 2 diabetes. We have identified a monoclonal antibody that inhibits GCGR, a class B G-protein coupled receptor (GPCR), through a unique allosteric mechanism. Receptor inhibition is mediated by the binding of this antibody to two distinct sites that lie outside of the glucagon binding cleft. One site consists of a patch of residues that are surface-exposed on the face of the extracellular domain (ECD) opposite the ligand-binding cleft, whereas the second binding site consists of residues in the αA helix of the ECD. A docking model suggests that the antibody does not occlude the ligand-binding cleft. We solved the crystal structure of GCGR ECD containing a naturally occurring G40S mutation and found a shift in the register of the αA helix that prevents antibody binding. We also found that alterations in the αA helix impact the normal function of GCGR. We present a model for the allosteric inhibition of GCGR by a monoclonal antibody that may form the basis for the development of allosteric modulators for the treatment of diabetes and other class B GPCR-related diseases.

Keywords: Antibody Engineering; Diabetes; G Protein-coupled Receptors (GPCR); Glucose Metabolism; Structural Biology.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Regulation
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / immunology*
  • Crystallography, X-Ray
  • Extracellular Space / metabolism
  • Humans
  • Male
  • Mice
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / chemistry*
  • Receptors, Glucagon / immunology*


  • Antibodies, Monoclonal
  • Receptors, Glucagon

Associated data

  • PDB/4LEX
  • PDB/4LF3