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

Nat Struct Mol Biol. 2005 Sep;12(9):822-3. doi: 10.1038/nsmb971. Epub 2005 Aug 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / chemistry*
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Coumarins / chemistry
  • Coumarins / metabolism*
  • Cytochrome P-450 CYP2A6
  • Humans
  • Methoxsalen / chemistry
  • Methoxsalen / metabolism*
  • Microsomes / enzymology*
  • Mixed Function Oxygenases / chemistry*
  • Mixed Function Oxygenases / metabolism*
  • Models, Molecular
  • Protein Structure, Tertiary


  • Coumarins
  • coumarin
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • Methoxsalen

Associated data

  • PDB/1PQ2
  • PDB/1R9O
  • PDB/1TQN
  • PDB/1Z10
  • PDB/1Z11