title: Possible pathway(s) of metyrapone egress from the active site of cytochrome P450 3A4: a molecular dynamics simulation.
abstract: To identify a possible pathway(s) for metyrapone egress from the active site of P450 3A4, a 5-ns conventional molecular dynamics simulation followed by steered molecular dynamics simulations was performed on the complex with metyrapone. The steered molecular dynamics simulations showed that metyrapone egress via channel 1, threading through the B-C loop, only required a relatively small rupture force and small displacement of residues, whereas egress via the third channel, between helix I and helices F' and G', required a relatively large force and perturbation of helices I, B', and C. The conventional dynamics simulation indicated that channel 2, located between the beta1 sheet, B-B' loop, and F'-G' region, is closed because of the movement of residues in the mouth of this channel. The findings suggest that channel 1 can be used for metyrapone egress, whereas both channel 2 and channel 3 have a low probability of serving as an exit channel for metyrapone. In addition, residues F108 and I120 appear to act as two gatekeepers to prevent the inhibitor from leaving the active site. These results are in agreement with previous site-directed mutagenesis experiments.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: James R
authors.initials: JR
authors.lastname: Halpert
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D030562:Databases, Protein; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008797:Metyrapone / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008797:Metyrapone