Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor

J Biol Chem. 2010 Jan 1;285(1):723-30. doi: 10.1074/jbc.M109.033829. Epub 2009 Oct 27.

Abstract

GLP-1 (glucagon-like peptide-1) is an incretin released from intestinal L-cells in response to food intake. Activation of the GLP-1 receptor potentiates the synthesis and release of insulin from pancreatic beta-cells in a glucose-dependent manner. The GLP-1 receptor belongs to class B of the G-protein-coupled receptors, a subfamily characterized by a large N-terminal extracellular ligand binding domain. Exendin-4 and GLP-1 are 50% identical, and exendin-4 is a full agonist with similar affinity and potency for the GLP-1 receptor. We recently solved the crystal structure of the GLP-1 receptor extracellular domain in complex with the competitive antagonist exendin-4(9-39). Interestingly, the isolated extracellular domain binds exendin-4 with much higher affinity than the endogenous agonist GLP-1. Here, we have solved the crystal structure of the extracellular domain in complex with GLP-1 to 2.1 Aresolution. The structure shows that important hydrophobic ligand-receptor interactions are conserved in agonist- and antagonist-bound forms of the extracellular domain, but certain residues in the ligand-binding site adopt a GLP-1-specific conformation. GLP-1 is a kinked but continuous alpha-helix from Thr(13) to Val(33) when bound to the extracellular domain. We supplemented the crystal structure with site-directed mutagenesis to link the structural information of the isolated extracellular domain with the binding properties of the full-length receptor. The data support the existence of differences in the binding modes of GLP-1 and exendin-4 on the full-length GLP-1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Crystallography, X-Ray
  • Extracellular Space / metabolism*
  • Glucagon-Like Peptide 1 / chemistry*
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Glucagon / chemistry*
  • Receptors, Glucagon / metabolism
  • Solutions

Substances

  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Mutant Proteins
  • Receptors, Glucagon
  • Solutions
  • Glucagon-Like Peptide 1

Associated data

  • PDB/3IOL