Mammalian microsomal cytochrome P450 monooxygenase: Structural adaptationsfor membrane binding and functional diversity

Microsomal cytochrome P450s participate in xenobiotic detoxification, proca rcinogen 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 place s the entrance of the putative substrate access channel in or near the memb rane and orients the face of the protein proximal to the heme cofactor perp endicular to the plane of the membrane for interaction with the P450 reduct ase. This structure offers a template for modeling other mammalian P450s an d should aid drug discovery and the prediction of drug-drug interactions.