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J. Biol. Chem., Vol. 279, Issue 37, 38091-38094, September 10, 2004

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The Structure of Human Microsomal Cytochrome P450 3A4 Determined by X-ray Crystallography to 2.05-Å Resolution^*

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

From the Department of Molecular and Experimental Medicine and ^¶Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

The structure of P450 3A4 was determined by x-ray crystallography to 2.05-Å resolution. P450 3A4 catalyzes the metabolic clearance of a large number of clinically used drugs, and a number of adverse drug-drug interactions reflect the inhibition or induction of the enzyme. P450 3A4 exhibits a relatively large substrate-binding cavity that is consistent with its capacity to oxidize bulky substrates such as cyclosporin, statins, taxanes, and macrolide antibiotics. Family 3A P450s also exhibit unusual kinetic characteristics that suggest simultaneous occupancy by smaller substrates. Although the active site volume is similar to that of P450 2C8 (PDB code: 1PQ2), the shape of the active site cavity differs considerably due to differences in the folding and packing of portions of the protein that form the cavity. Compared with P450 2C8, the active site cavity of 3A4 is much larger near the heme iron. The lower constraints on the motions of small substrates near the site of oxygen activation may diminish the efficiency of substrate oxidation, which may, in turn, be improved by space restrictions imposed by the presence of a second substrate molecule. The structure of P450 3A4 should facilitate a better understanding of the substrate selectivity of the enzyme.

Received for publication, June 22, 2004 , and in revised form, July 14, 2004.

^* This work was supported by Pfizer Global Research & Development and National Institutes of Health Grant GM031001 (to E. F. J.). Facilities for computer-assisted sequence analysis, DNA sequencing, and the synthesis of oligonucleotides were supported in part by General Clinical Research Center Grant M01 RR00833 and by the Sam and Rose Stein Charitable Trust. Portions of this research were carried out at the Stanford Synchrotron Radiation Laboratory (SSRL), a national user facility operated by Stanford University on behalf of the United States Department of Energy, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program, and the National Institute of General Medical Sciences. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, Materials Sciences Division, of the United States Department of Energy under Contract number DE-AC03-76SF00098 at the Lawrence Berkeley National Laboratory. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

The atomic coordinates and structure factors (code 1TQN) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

These authors contributed equally to this work.

^|| To whom to correspondence may be addressed: Dept. of Molecular Biology, The Scripps Research Inst., 10550 N. Torrey Pines Rd., MB8, La Jolla, CA 92037. Tel.: 858-784-8738; Fax: 858-784-2857; E-mail: dave{at}scripps.edu. ** To whom correspondence may be addressed: Dept. of Molecular and Experimental Medicine, The Scripps Research Inst., 10550 N. Torrey Pines Rd., MEM-255, La Jolla, CA 92037. Tel.: 858-784-7918; Fax: 858-784-7978; E-mail: johnson{at}scripps.edu.

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