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J. Biol. Chem., Vol. 282, Issue 23, 17306-17313, June 8, 2007

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Structure of the Human Lung Cytochrome P450 2A13^*

Brian D. Smith, Jason L. Sanders, Patrick R. Porubsky, Gerald H. Lushington, C. David Stout^¶, and Emily E. Scott¹

From the Department of Medicinal Chemistry and Molecular Graphics & Modeling Laboratory, University of Kansas, Lawrence, Kansas 66045 and the ^¶Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

The human lung cytochrome P450 2A13 (CYP2A13) activates the nicotine-derived procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) into DNA-altering compounds that cause lung cancer. Another cytochrome P450, CYP2A6, is also present in human lung, but at much lower levels. Although these two enzymes are 93.5% identical, CYP2A13 metabolizes NNK with much lower K_m values than does CYP2A6. To investigate the structural differences between these two enzymes the structure of CYP2A13 was determined to 2.35Å by x-ray crystallography and compared with structures of CYP2A6. As expected, the overall CYP2A13 and CYP2A6 structures are very similar with an average root mean square deviation of 0.5Å for the C atoms. Like CYP2A6, the CYP2A13 active site cavity is small and highly hydrophobic with a cluster of Phe residues composing the active site roof. Active site residue Asn²⁹⁷ is positioned to hydrogen bond with an adventitious ligand, identified as indole. Amino acid differences between CYP2A6 and CYP2A13 at positions 117, 300, 301, and 208 relate to different orientations of the ligand plane in the two protein structures and may underlie the significant variations observed in binding and catalysis of many CYP2A ligands. In addition, docking studies suggest that residues 365 and 366 may also contribute to differences in NNK metabolism.

Received for publication, March 19, 2007 , and in revised form, April 2, 2007.

^* This work was supported by the National Institutes of Health Grants RR016475 (to J. L. S. and P. R. P.), GM61545 (to C. D. S.), RR017708 (to E. E. S.), and GM076343 (to E. E. S.). 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 Fig. S1.

¹ To whom correspondence should be addressed: 1251 Wescoe Hall Dr., Lawrence, KS 66045. Tel.: 785-864-5559; Fax: 785-864-5326; E-mail: eescott{at}ku.edu.

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