1r9o

Publication Abstract from PubMed

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.

The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A resolution.,Wester MR, Yano JK, Schoch GA, Yang C, Griffin KJ, Stout CD, Johnson EF J Biol Chem. 2004 Aug 20;279(34):35630-7. Epub 2004 Jun 4. PMID:15181000^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.