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.

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@article{Wester2004TheSO, title={The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A resolution.}, author={Michael R Wester and Jason K Yano and Guillaume A. Schoch and Christine C Yang and Keith J Griffin and Charles David Stout and Eric F Johnson}, journal={The Journal of biological chemistry}, year={2004}, volume={279 34}, pages={35630-7} }