A model for receptor-peptide binding at the glucagon-like peptide-1 (GLP-1) receptor through the analysis of truncated ligands and receptors

Br J Pharmacol. 2003 Sep;140(2):339-46. doi: 10.1038/sj.bjp.0705453. Epub 2003 Aug 26.


1. The receptor for glucagon-like peptide-1 (GLP-1) can be activated by both its physiological hormone and a peptide discovered in the venom of the Gila Monster, exendin-4, which shows promise as an antidiabetic agent. 2. Exendin-4 displays receptor-binding properties not observed for GLP-1. Firstly, exendin-4 can be truncated by up to eight residues at its N-terminus without a significant loss of affinity. Secondly, exendin-4 maintains high affinity for the isolated N-terminal domain of the receptor, suggesting that exendin-4 makes additional contacts with this domain of the receptor, which nullify the requirement for ligand-receptor interactions involving the extracellular loops and/or transmembrane helices of the receptor's core domain. 3. In order to further understand the nature of the receptor-peptide interaction, a variety of full length and truncated peptide analogues were used to quantify the contribution of each distinct region of exendin-4 and GLP-1 to receptor affinity. 4. Our data show that, for both exendin-4 and GLP-1, the primary interaction is between the putative helical region of the peptide and the extracellular N-terminal domain of the receptor. 5. However, we demonstrate that the contribution to receptor affinity provided by the N-terminal segment of GLP-1 is greater than that of exendin-4, while the C-terminal nine residue extension of exendin-4, absent in GLP-1, forms a compensatory interaction with the N-terminal domain of the receptor. 6. We describe a peptide-receptor binding model to account for these data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Exenatide
  • Glucagon / chemistry
  • Glucagon / genetics
  • Glucagon / metabolism*
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Kinetics
  • Ligands
  • Models, Biological
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / metabolism*
  • Plasmids / genetics
  • Protein Binding
  • Protein Precursors / chemistry
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • Receptors, Glucagon / chemistry
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism*
  • Sequence Homology, Amino Acid
  • Transfection
  • Venoms / chemistry
  • Venoms / genetics
  • Venoms / metabolism*


  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Ligands
  • Peptide Fragments
  • Peptides
  • Protein Precursors
  • Receptors, Glucagon
  • Venoms
  • Glucagon-Like Peptide 1
  • Glucagon
  • Exenatide