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Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen

Nature Structural & Molecular Biologyvolume 12pages822823 (2005) | Download Citation

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Abstract

Human microsomal cytochrome P450 2A6 (CYP2A6) contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. The CYP2A6 structure shows a compact, hydrophobic active site with one hydrogen bond donor, Asn297, that orients coumarin for regioselective oxidation. The inhibitor methoxsalen effectively fills the active site cavity without substantially perturbing the structure. The structure should aid the design of inhibitors to reduce smoking and tobacco-related cancers.

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  • 14 August 2005

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Notes

  1. 1.

    Note: In the version of this article initially published online, a sentence in the fifth paragraph of the article was incorrectly transcribed. The sentence originally read, “The furan oxygen is positioned closer to the nearest carbon than to the heme iron, and the inhibitor is not positioned well for aromatic hydroxylation or epoxidation.” The error has been corrected for the HTML and the print versions of the article.

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Acknowledgements

This work was supported by the US National Institutes of Health grant GM031001 (to E.F.J.) and fellowship 12FT-0185 from the Tobacco-Related Disease Research Program (to J.K.Y.). Facilities for computer-assisted sequence analysis, DNA sequencing and the synthesis of oligonucleotides were supported in part by the 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 US 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 US National Institutes of Health, National Center for Research Resources, Biomedical Technology Program and National Institute of General Medical Sciences. The authors thank F. Gonzalez (National Cancer Institute) for kindly providing the CYP2A6 cDNA.

Author information

Affiliations

  1. Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, 92037, California, USA

    • Jason K Yano
    • , Mei-Hui Hsu
    • , Keith J Griffin
    •  & Eric F Johnson
  2. Department of Molecular Biology, Scripps Research Institute, La Jolla, 92037, California, USA

    • C David Stout

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to C David Stout or Eric F Johnson.

Supplementary information

  1. Supplementary Fig. 1

    The overall fold of CYP2A6 and comparison with CYP2C8. (PDF 170 kb)

  2. Supplementary Fig. 2

    Residue interactions that contribute to a compact polypeptide fold. (PDF 123 kb)

  3. Supplementary Fig. 3

    Wall-eyed stereo view of the potential hydrogen bonding of Asn297. (PDF 41 kb)

  4. Supplementary Table 1

    Data collection and refinement statistics. (PDF 28 kb)

  5. Supplementary Methods (PDF 92 kb)

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https://doi.org/10.1038/nsmb971

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