3IOL

Crystal structure of Glucagon-Like Peptide-1 in complex with the extracellular domain of the Glucagon-Like Peptide-1 Receptor

Summary for 3IOL

• Entry DOI: 10.2210/pdb3iol/pdb
• Related: 3C59 3C5T
• Descriptor: Glucagon-like peptide 1 receptor, Glucagon, decyl 4-O-alpha-D-glucopyranosyl-1-thio-beta-D-glucopyranoside, ... (4 entities in total)
• Functional Keywords: receptor-ligand complex, cell membrane, disulfide bond, g-protein coupled receptor, glycoprotein, membrane, receptor, transducer, transmembrane, amidation, cleavage on pair of basic residues, hormone, 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: P01275
• Total number of polymer chains: 2
• Total formula weight: 18597.64

Authors

Reedtz-Runge, S. (deposition date: 2009-08-14, release date: 2009-10-27, Last modification date: 2024-10-09)

Primary citation

Underwood, C.R.,Garibay, P.,Knudsen, L.B.,Hastrup, S.,Peters, G.H.,Rudolph, R.,Reedtz-Runge, S.
Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor
J.Biol.Chem., 285:723-730, 2010

PubMed 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.

PubMed: 19861722
DOI: 10.1074/jbc.M109.033829

Experimental method

X-RAY DIFFRACTION (2.1 Å)