Possible pathway(s) of metyrapone egress from the active site of cytochrome P450 3A4: A molecular dynamics simulation
文献类型：期刊论文
| 作者 | Li, Weihua; Liu, Hong ; Luo, Xiaomin; Zhu, Weiliang; Tang, Yun; Halpert, James R.; Jiang, Hualiang
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| 刊名 | DRUG METABOLISM AND DISPOSITION
 |
| 出版日期 | 2007-04 |
| 卷号 | 35期号:4页码:689-696 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.106.014019 |
| 文献子类 | Article |
| 英文摘要 | 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 beta 1 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. |
| WOS关键词 | INDUCED CONFORMATIONAL-CHANGE ; PARTICLE MESH EWALD ; ACCESS CHANNELS ; HETEROTROPIC COOPERATIVITY ; CRYSTAL-STRUCTURE ; SUBSTRATES ENTER ; PRODUCTS EXIT ; MECHANISMS ; BINDING ; P450S |
| 资助项目 | NIGMS NIH HHS[R37 GM054995] ; NIGMS NIH HHS[GM54995] ; NIEHS NIH HHS[ES06676] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000245179100025 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273294]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Jiang, Hualiang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Discovery & Design, State Key Lab Drug Res,Grad Sch, Shanghai 201203, Peoples R China 2.Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77550 USA 3.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Weihua,Liu, Hong,Luo, Xiaomin,et al. Possible pathway(s) of metyrapone egress from the active site of cytochrome P450 3A4: A molecular dynamics simulation[J]. DRUG METABOLISM AND DISPOSITION,2007,35(4):689-696. |
| APA | Li, Weihua.,Liu, Hong.,Luo, Xiaomin.,Zhu, Weiliang.,Tang, Yun.,...&Jiang, Hualiang.(2007).Possible pathway(s) of metyrapone egress from the active site of cytochrome P450 3A4: A molecular dynamics simulation.DRUG METABOLISM AND DISPOSITION,35(4),689-696. |
| MLA | Li, Weihua,et al."Possible pathway(s) of metyrapone egress from the active site of cytochrome P450 3A4: A molecular dynamics simulation".DRUG METABOLISM AND DISPOSITION 35.4(2007):689-696. |
入库方式： OAI收割
来源：上海药物研究所
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