title: CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach.
abstract: We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.
authors.affiliation: Department of Vascular Biology, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK CM19 5AD.
authors.forename: Theo A
authors.initials: TA
authors.lastname: Berkhout
authors.forename: Frank E
authors.initials: FE
authors.lastname: Blaney
authors.forename: Angela M
authors.initials: AM
authors.lastname: Bridges
authors.forename: David G
authors.initials: DG
authors.lastname: Cooper
authors.forename: Ian T
authors.initials: IT
authors.lastname: Forbes
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Gribble
authors.forename: Pieter H E
authors.initials: PH
authors.lastname: Groot
authors.forename: Adam
authors.initials: A
authors.lastname: Hardy
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ife
authors.forename: Rejbinder
authors.initials: R
authors.lastname: Kaur
authors.forename: Kitty E
authors.initials: KE
authors.lastname: Moores
authors.forename: Helen
authors.initials: H
authors.lastname: Shillito
authors.forename: Jennifer
authors.initials: J
authors.lastname: Willetts
authors.forename: Jason
authors.initials: J
authors.lastname: Witherington
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002417:Cattle; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D006224:Cricetinae; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics; D040681:Structural Homology, Protein; D014162:Transfection
chemical_list: C515334:CCR2 protein, human; D007211:Indoles; D010880:Piperidines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D012243:Rhodopsin