Structural and Dynamical Basis of Broad Substrate Specificity, Catalytic Mechanism, and Inhibition of Cytochrome P450 3A4

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• 作者：Hwangseo Park ; Sangyoub Lee ; and Junghun Suh
• 刊名：Journal of the American Chemical Society
• 出版年：2005
• 出版时间：October 5, 2005
• 年：2005
• 卷：127
• 期：39
• 页码：13634 - 13642
• 全文大小：677K
• 年卷期：v.127,no.39(October 5, 2005)
• ISSN：1520-5126

文摘

Cytochrome P450 (CYP) 3A4 is responsible for the oxidative degradation of more than 50% ofclinically used drugs. By means of molecular dynamics simulations with the newly developed force fieldparameters for the heme-thiolate group and its dioxygen adduct, we examine the differences in structuraland dynamic properties between CYP3A4 in the resting form and its complexes with the substrateprogesterone and the inhibitor metyrapone. The results indicate that the broad substrate specificity ofCYP3A4 stems from the malleability of a loop (residues 211-218) that resides in the vicinity of the channelconnecting the active site and bulk solvent. However, the high-amplitude motion of the flexible loop isfound to be damped out upon binding of the inhibitor or the substrate in the active site. In the resting formof CYP3A4, a structural water molecule is bound to the sixth coordination position of the heme iron, stabilizingthe octahedral coordination geometry. In addition to the direct coordination of metyrapone to the hemeiron, the hydrogen bond interaction between the inhibitor carbonyl group and the side chain of Ser119 alsocontributes significantly to stabilizing the CYP3A4-metyrapone complex. On the other hand, progesteroneis stabilized in the active site by the formation of two hydrogen bonds with Ser119 and Arg106, as well asby the van der Waals interactions with the heme and hydrophobic residues. The structural and dynamicfeatures of the CYP3A4-progesterone complex indicate that the oxidative degradation of progesteroneoccurs through hydroxylation at the C16 position by the reactive oxygen coordinated to the heme iron.