2QKH

Crystal structure of the extracellular domain of human GIP receptor in complex with the hormone GIP

Summary for 2QKH

• Entry DOI: 10.2210/pdb2qkh/pdb
• Related PRD ID: PRD_900086
• Descriptor: Glucose-dependent insulinotropic polypeptide, Glucose-dependent insulinotropic polypeptide receptor, Cyclic 2,3-di-O-methyl-alpha-D-glucopyranose-(1-4)-2-O-methyl-alpha-D-glucopyranose-(1-4)-2,6-di-O-methyl-alpha-D-glucopyranose-(1-4)-2-O-methyl-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose-(1-4)-3-O-methyl-alpha-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: gpcr, incretin, hormone-gpcr complex, extracellular domain, ligand binding domain, ecd, glugacon receptor family, hormone recognition fold, diabetes, helix formation, cleavage on pair of basic residues, polymorphism, alternative splicing, g-protein coupled receptor, glycoprotein, membrane, transducer, transmembrane, signaling protein-hormone complex, signaling protein/hormone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 21782.85

Authors

Parthier, C.,Kleinschmidt, M.,Neumann, P.,Rudolph, R.,Manhart, S.,Schlenzig, D.,Fanghanel, J.,Rahfeld, J.-U.,Demuth, H.-U.,Stubbs, M.T. (deposition date: 2007-07-11, release date: 2007-08-14, Last modification date: 2024-10-30)

Primary citation

Parthier, C.,Kleinschmidt, M.,Neumann, P.,Rudolph, R.,Manhart, S.,Schlenzig, D.,Fanghanel, J.,Rahfeld, J.-U.,Demuth, H.-U.,Stubbs, M.T.
Crystal structure of the incretin-bound extracellular domain of a G protein-coupled receptor
Proc.Natl.Acad.Sci.Usa, 104:13942-13947, 2007

PubMed 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.

PubMed: 17715056
DOI: 10.1073/pnas.0706404104

Experimental method

X-RAY DIFFRACTION (1.9 Å)