title: Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen.
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.
authors.affiliation: Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Yano
authors.forename: Mei-Hui
authors.initials: MH
authors.lastname: Hsu
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Griffin
authors.forename: C David
authors.initials: CD
authors.lastname: Stout
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000378:metabolism*; D003374:Coumarins / Q000737:chemistry / Q000378:metabolism*; D065637:Cytochrome P-450 CYP2A6; D006801:Humans; D008730:Methoxsalen / Q000737:chemistry / Q000378:metabolism*; D008861:Microsomes / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary
chemical_list: D003374:Coumarins; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D008730:Methoxsalen