title: Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain.
abstract: The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B1 of the seven-transmembrane G protein-coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is involved in glucose homeostasis, and activation of GLP-1R in the plasma membrane of pancreatic beta-cells potentiates glucose-dependent insulin secretion. The N-terminal extracellular domain (nGLP-1R) is an important ligand binding domain that binds GLP-1 and the homologous peptide Exendin-4 with differential affinity. Exendin-4 has a C-terminal extension of nine amino acid residues known as the "Trp cage", which is absent in GLP-1. The Trp cage was believed to interact with nGLP-1R and thereby explain the superior affinity of Exendin-4. However, the molecular details that govern ligand binding and specificity of nGLP-1R remain undefined. Here we report the crystal structure of human nGLP-1R in complex with the antagonist Exendin-4(9-39) solved by the multiwavelength anomalous dispersion method to 2.2A resolution. The structure reveals that Exendin-4(9-39) is an amphipathic alpha-helix forming both hydrophobic and hydrophilic interactions with nGLP-1R. The Trp cage of Exendin-4 is not involved in binding to nGLP-1R. The hydrophobic binding site of nGLP-1R is defined by discontinuous segments including primarily a well defined alpha-helix in the N terminus of nGLP-1R and a loop between two antiparallel beta-strands. The structure provides for the first time detailed molecular insight into ligand binding of the human GLP-1 receptor, an established target for treatment of type 2 diabetes.
authors.affiliation: Department of Structure and Biophysical Chemistry, Novo Nordisk, 2760 Måløv, Denmark. sffr@novonordisk.com
authors.forename: Steffen
authors.initials: S
authors.lastname: Runge
authors.forename: Henning
authors.initials: H
authors.lastname: Thøgersen
authors.forename: Kjeld
authors.initials: K
authors.lastname: Madsen
authors.forename: Jesper
authors.initials: J
authors.lastname: Lau
authors.forename: Rainer
authors.initials: R
authors.lastname: Rudolph
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray / Q000379:methods; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018027:Receptors, Glucagon / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014364:Tryptophan / Q000737:chemistry; D014688:Venoms / Q000737:chemistry
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D014364:Tryptophan; D000077270:Exenatide