title: Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor.
abstract: Incretins, endogenous polypeptide hormones released in response to food intake, potentiate insulin secretion from pancreatic beta cells after oral glucose ingestion (the incretin effect). This response is signaled by the two peptide hormones glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) and glucagon-like peptide 1 through binding and activation of their cognate class 2 G protein-coupled receptors (GPCRs). Because the incretin effect is lost or significantly reduced in patients with type 2 diabetes mellitus, glucagon-like peptide 1 and GIP have attracted considerable attention for their potential in antidiabetic therapy. A paucity of structural information precludes a detailed understanding of the processes of hormone binding and receptor activation, hampering efforts to develop novel pharmaceuticals. Here we report the crystal structure of the complex of human GIP receptor extracellular domain (ECD) with its agonist, the incretin GIP(1-42). The hormone binds in an alpha-helical conformation in a surface groove of the ECD largely through hydrophobic interactions. The N-terminal ligand residues would remain free to interact with other parts of the receptor. Thermodynamic data suggest that binding is concomitant with structural organization of the hormone, resulting in a complex mode of receptor-ligand recognition. The presentation of a well structured, alpha-helical ligand by the ECD is expected to be conserved among other hormone receptors of this class.
authors: Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, D-06120 Halle (Saale), Germany.
authors: Christoph
authors: C
authors: Parthier
authors: Martin
authors: M
authors: Kleinschmidt
authors: Piotr
authors: P
authors: Neumann
authors: Rainer
authors: R
authors: Rudolph
authors: Susanne
authors: S
authors: Manhart
authors: Dagmar
authors: D
authors: Schlenzig
authors: Jörg
authors: J
authors: Fanghänel
authors: Jens-Ulrich
authors: JU
authors: Rahfeld
authors: Hans-Ulrich
authors: HU
authors: Demuth
authors: Milton T
authors: MT
authors: Stubbs
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D036361:Peptide Hormones / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D004220:Disulfides; D007328:Insulin; D008024:Ligands; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled
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