2p85
Structure of Human Lung Cytochrome P450 2A13 with indole bound in two alternate conformations
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OverviewOverview
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 2.35A 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 0.5A for the Calpha 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, Asn(297) 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.
About this StructureAbout this Structure
2P85 is a Single protein structure of sequence from Homo sapiens with HEM and IND as ligands. Active as Unspecific monooxygenase, with EC number 1.14.14.1 Full crystallographic information is available from OCA.
ReferenceReference
Structure of the human lung cytochrome P450 2A13., Smith BD, Sanders JL, Porubsky PR, Lushington GH, Stout CD, Scott EE, J Biol Chem. 2007 Jun 8;282(23):17306-13. Epub 2007 Apr 11. PMID:17428784
Page seeded by OCA on Mon Nov 12 23:21:28 2007