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Papers In Press, published online ahead of print June 4, 2004
J. Biol. Chem, 10.1074/jbc.M405427200
Submitted on May 17, 2004
Revised on June 3, 2004
Accepted on June 4, 2004

The structure of human microsomal cytochrome P450 2C9 complexed with flurbiprofen at 2.0 A resolution

Michael R. Wester, Jason K. Yano, Guillaume A. Schoch, Christine Yang, Keith J. Griffin, C. David Stout, and Eric F. Johnson

Molecular and Experimental Medicine, MEM-255, The Scripps Research Institute, La Jolla, CA 92037

Corresponding Author: johnson{at}scripps.edu

The structure of human P450 2C9 complexed with flurbiprofen was determined to 2.0 Å 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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