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The Structure of Human Cytochrome P450 2C9 Complexed with Flurbiprofen at 2.0-Å Resolution

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Wester, Michael R., Yano, Jason K., Schoch, Guillaume A., Yang, Christine, Griffin, Keith J., Stout, C. David, Johnson, Eric F.·2004·Journal of Biological Chemistry

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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Authors
Wester, M. R., Yano, J. K., Schoch, G. A., Yang, C., Griffin, K. J., Stout, C. D., & Johnson, E. F.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2004-08
Volume
279
Issue
34
Pages
35630-35637
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2154598050
Cited by
440
References
0
FWCI
27.69
Type
journal article
Language
en
Open access
hybrid

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