title: The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A resolution.
abstract: The structure of human P450 2C9 complexed with flurbiprofen was determined to 2.0 A by x-ray crystallography. In contrast to other structurally characterized P450 2C enzymes, 2C5, 2C8, and a 2C9 chimera, the native catalytic domain of P450 2C9 differs significantly in the conformation of the helix F to helix G region and exhibits an extra turn at the N terminus of helix A. In addition, a distinct conformation of the helix B to helix C region allows Arg-108 to hydrogen bond with Asp-293 and Asn-289 on helix I and to interact directly with the carboxylate of flurbiprofen. These interactions position the substrate for regioselective oxidation in a relatively large active site cavity and are likely to account for the high catalytic efficiency exhibited by P450 2C9 for the regioselective oxidation of several anionic non-steroidal anti-inflammatory drugs. The structure provides a basis for interpretation of a number of observations regarding the substrate selectivity of P450 2C9 and the observed effects of mutations on catalysis.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wester
authors.forename: Jason K
authors.initials: JK
authors.lastname: Yano
authors.forename: Guillaume A
authors.initials: GA
authors.lastname: Schoch
authors.forename: Christine
authors.initials: C
authors.lastname: Yang
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Griffin
authors.forename: C David
authors.initials: CD
authors.lastname: Stout
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
mesh_terms: D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D020134:Catalytic Domain; D065729:Cytochrome P-450 CYP2C9; D005480:Flurbiprofen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D005480:Flurbiprofen; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases