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J. Biol. Chem., Vol. 282, Issue 19, 14348-14355, May 11, 2007

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Adaptations for the Oxidation of Polycyclic Aromatic Hydrocarbons Exhibited by the Structure of Human P450 1A2^*

Stefaan Sansen, Jason K. Yano¹, Rosamund L. Reynald, Guillaume A. Schoch², Keith J. Griffin, C. David Stout³, and Eric F. Johnson⁴

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

Microsomal cytochrome P450 family 1 enzymes play prominent roles in xenobiotic detoxication and procarcinogen activation. P450 1A2 is the principal cytochrome P450 family 1 enzyme expressed in human liver and participates extensively in drug oxidations. This enzyme is also of great importance in the bioactivation of mutagens, including the N-hydroxylation of arylamines. P450-catalyzed reactions involve a wide range of substrates, and this versatility is reflected in a structural diversity evident in the active sites of available P450 structures. Here, we present the structure of human P450 1A2 in complex with the inhibitor -naphthoflavone, determined to a resolution of 1.95 Å. -Naphthoflavone is bound in the active site above the distal surface of the heme prosthetic group. The structure reveals a compact, closed active site cavity that is highly adapted for the positioning and oxidation of relatively large, planar substrates. This unique topology is clearly distinct from known active site architectures of P450 family 2 and 3 enzymes and demonstrates how P450 family 1 enzymes have evolved to catalyze efficiently polycyclic aromatic hydrocarbon oxidation. This report provides the first structure of a microsomal P450 from family 1 and offers a template to study further structure-function relationships of alternative substrates and other cytochrome P450 family 1 members.

Received for publication, December 21, 2006 , and in revised form, February 2, 2007.

The atomic coordinates and structure factors (code 2HI4) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Pfizer Global Research and Development, National Institutes of Health Grant GM031001 (to E. F. J.) and the Sam and Rose Stein Charitable Trust. 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 a supplemental table and two figures.

This article was selected as a Paper of the Week.

¹ Present address: Dept. of Structural Biology, Takeda San Diego, 10410 Science Center Dr., San Diego, Ca 92121.

² Present address: F. Hoffmann-La Roche Ltd., Pharma Discovery Research Basel, CH-4070 Basel, Switzerland.

³ To whom correspondence may be addressed: Dept. of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., MB8, La Jolla, CA 92037. Tel.: 858-784-8738; Fax: 858-784-2857; E-mail: dave{at}scripps.edu. ⁴ To whom correspondence may be addressed: Dept. of Molecular and Experimental Medicine, The Scripps Research Institute, 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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