3C59

Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain

Summary for 3C59

• Entry DOI: 10.2210/pdb3c59/pdb
• Related: 3C5T
• Descriptor: Glucagon-like peptide 1 receptor, Exendin-4, decyl 4-O-alpha-D-glucopyranosyl-1-thio-beta-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: ligand-bound g protein-coupled receptor, g-protein coupled receptor, glycoprotein, membrane, transducer, transmembrane, amidation, cleavage on pair of basic residues, secreted, signaling protein-signaling protein complex, signaling protein/signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane ; Multi- pass membrane protein : P43220; Secreted: P26349
• Total number of polymer chains: 2
• Total formula weight: 18310.06

Authors

Runge, S. (deposition date: 2008-01-31, release date: 2008-02-19, Last modification date: 2024-11-20)

Primary citation

Runge, S.,Thogersen, H.,Madsen, K.,Lau, J.,Rudolph, R.
Crystal Structure of the Ligand-bound Glucagon-like Peptide-1 Receptor Extracellular Domain
J.Biol.Chem., 283:11340-11347, 2008

PubMed 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.

PubMed: 18287102
DOI: 10.1074/jbc.M708740200

Experimental method

X-RAY DIFFRACTION (2.3 Å)