Nature Structural & Molecular Biology
12, 822 - 823 (2005)
Published online: 7 August 2005; Corrected online: 14 August 2005 | doi:10.1038/nsmb971
Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalenJason K Yano1, Mei-Hui Hsu1, Keith J Griffin1, C David Stout2
& Eric F Johnson11
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037, USA. 2
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
Correspondence should be addressed to Eric F Johnson johnson@scripps.edu or C David Stout dave@scripps.edu 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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