title: Intermolecular interactions between peptidic and nonpeptidic agonists and the third extracellular loop of the cholecystokinin 1 receptor.
abstract: 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, CCK(1)-R(329-357), and the synthetic agonists Ace-Trp-Lys[NH(epsilon)CONH-o-(MePh)]-Asp-MePhe-NH(2) (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 CCK(1)-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/CCK(1)-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 structure-activity relationship of analogues and mutagenesis data for the CCK(1)-R selective antagonist L-364,718.
authors.affiliation: Department of Chemistry, Division of Biology & Medicine, Brown University, Providence, RI 02912, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Giragossian
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Sugg
authors.forename: Jerzy R
authors.initials: JR
authors.lastname: Szewczyk
authors.forename: Dale F
authors.initials: DF
authors.lastname: Mierke
mesh_terms: D001570:Benzodiazepinones / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D020109:Devazepide / Q000737:chemistry; D006801:Humans; D007536:Isomerism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001570:Benzodiazepinones; C476596:GI 0122; C476595:GI 5269; D008024:Ligands; D009842:Oligopeptides; D010446:Peptide Fragments; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D020109:Devazepide