Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity.
Microsomal cytochrome P450s participate in xenobiotic detoxification, procarcinogen activation, and steroid hormone synthesis. The first structure of a mammalian microsomal P450 suggests that the association of P450s with the endoplasmic reticulum involves a hydrophobic surface of the protein formed by noncontiguous portions of the polypeptide chain. This interaction places the entrance of the putative substrate access channel in or near the membrane and orients the face of the protein proximal to the heme cofactor perpendicular to the plane of the membrane for interaction with the P450 reductase. This structure offers a template for modeling other mammalian P450s and should aid drug discovery and the prediction of drug-drug interactions.
Williams
P A
PA
Department of Molecular Biology MB-8, Scripps Research Institute, La Jolla, California 92037, USA.
Cosme
J
J
Sridhar
V
V
Johnson
E F
EF
McRee
D E
DE
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006418:Heme / Q000378:metabolism; D008322:Mammals; D008861:Microsomes / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000378:metabolism
D006418:Heme; D003577:Cytochrome P-450 Enzyme System; C065407:CYP2C5 protein, Oryctolagus cuniculus; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase