4EJI

Human Cytochrome P450 2A13 in complex with two molecules of 4-(methylnitrosamino)-1-(3-puridyl)-1-butanone

Summary for 4EJI

• Entry DOI: 10.2210/pdb4eji/pdb
• Related: 2P85 3T3S 4EJG 4EJH 4EJJ
• Descriptor: Cytochrome P450 2A13, PROTOPORPHYRIN IX CONTAINING FE, 4-[methyl(nitroso)amino]-1-(pyridin-3-yl)butan-1-one, ... (4 entities in total)
• Functional Keywords: cyp2a13, cytochrome p450 2a13, p450 2a13, heme protein, monooxygenase, drug metabolism, xenobiotic metabolism, endoplasmic reticulum, membrane, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: Q16696
• Total number of polymer chains: 1
• Total formula weight: 55835.70

Authors

DeVore, N.M.,Scott, E.E. (deposition date: 2012-04-06, release date: 2012-06-06, Last modification date: 2023-09-13)

Primary citation

DeVore, N.M.,Scott, E.E.
Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone binding and access channel in human cytochrome P450 2A6 and 2A13 enzymes.
J.Biol.Chem., 287:26576-26585, 2012

PubMed Abstract: Cytochromes P450 (CYP) from the 2A subfamily are known for their roles in the metabolism of nicotine, the addictive agent in tobacco, and activation of the tobacco procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Although both the hepatic CYP2A6 and respiratory CYP2A13 enzymes metabolize these compounds, CYP2A13 does so with much higher catalytic efficiency, but the structural basis for this has been unclear. X-ray structures of nicotine complexes with CYP2A13 (2.5 Å) and CYP2A6 (2.3 Å) yield a structural rationale for the preferential binding of nicotine to CYP2A13. Additional structures of CYP2A13 with NNK reveal either a single NNK molecule in the active site with orientations corresponding to metabolites known to form DNA adducts and initiate lung cancer (2.35 Å) or with two molecules of NNK bound (2.1 Å): one in the active site and one in a more distal staging site. Finally, in contrast to prior CYP2A structures with enclosed active sites, CYP2A13 conformations were solved that adopt both open and intermediate conformations resulting from an ∼2.5 Å movement of the F to G helices. This channel occurs in the same region where the second, distal NNK molecule is bound, suggesting that the channel may be used for ligand entry and/or exit from the active site. Altogether these structures provide multiple new snapshots of CYP2A13 conformations that assist in understanding the binding and activation of an important human carcinogen, as well as critical comparisons in the binding of nicotine, one of the most widely used and highly addictive drugs in human use.

PubMed: 22700965
DOI: 10.1074/jbc.M112.372813

Experimental method

X-RAY DIFFRACTION (2.1 Å)