Intermolecular interactions between peptidic and nonpeptidic agonists and the third extracellular loop of the cholecystokinin 1 receptor.

Intermolecular interactions were determined between a synthetic peptide corresponding to the third extracellular loop and several residues from the adjoining sixth and seventh transmembrane domains of the human cholecystokinin-1 receptor, CCK1-R(329−357), and the synthetic agonists Ace-Trp-Lys[NHeCONH-o-(MePh)]-Asp-MePhe-NH2 (GI5269) and the C1 N-isopropyl-N−(4-methoxyphenyl)acetamide derivative of 3-(1H-Indazol-3ylmethyl)-3-methyl-5-pyridin-3-yl-1,5-benzodiazepine (GI0122), using high-resolution nuclear magnetic resonance spectroscopy and computer simulations. Addition of the ligands to CCK1-R(329−357) in an aqueous solution of DPC micelles produced a number of intermolecular nuclear Overhauser enhancements (NOEs) to residues in TMs 6 and 7 of the receptor fragment. NOE-restrained molecular models of the GI5269 and GI0122/CCK1-R complexes provide evidence for overlapping ligand-binding sites for peptidic and nonpeptidic agonists. The proposed binding modes of GI5269 and GI0122 are supported by the struct...