Possible pathway(s) of testosterone egress from the active site of cytochrome P4502B1: A steered molecular dynamics simulation
文献类型：期刊论文
| 作者 | Li, WH; Liu, H ; Scott, EE; Grater, F; Halpert, JR; Luo, XM; Shen, JH; Jiang, HL
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2005-07 |
| 卷号 | 33期号:7页码:910-919 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.105.004200 |
| 文献子类 | Article |
| 英文摘要 | To probe the possible substrate exit channel(s) in cytochrome P450 (P450) 2B1 and to clarify the role of residues previously identified by site-directed mutagenesis, a homology model was constructed based on the X-ray crystal structure of a P450 2B4-inhibitor complex. Testosterone was docked into the active site of P450 2B1 and was then pulled out through three putative channels using steered molecular dynamics simulations. The results indicated that of the three channels, the "solvent channel," lined by helices E, F, and I and the beta 3 hairpin, required the largest rupture force and backbone motion, which rendered it unlikely as an exit route. The relatively small rupture forces and backbone motions for the other two channels suggested them as possible candidates for testosterone passage. The opening of channel 1, located between helices G and I and the B '-C loop, is characterized by rotation of the aromatic ring of Phe297 together with a bending of the B'-C loop. The opening of channel 2, penetrating through the B'-C loop/B' helix, is achieved by an expansion of this region and a small displacement of the backbone. Interestingly, during the egress of testosterone along channel 1, Phe297 and Phe108 appear to act as two clamps to stabilize testosterone binding and prevent it from leaving the active site. Phe115 acts as a gatekeeper for channel 2. These results are in agreement with previous site-directed mutagenesis experiments. |
| WOS关键词 | SUBSTRATE RECOGNITION ; CRYSTAL-STRUCTURE ; BINDING ; RESOLUTION ; MUTAGENESIS ; P450BM-3 ; PROTEINS ; ACID ; MECHANISM ; RESIDUES |
| 资助项目 | NIEHS NIH HHS[ES03619] ; NIEHS NIH HHS[ES06676] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000229842500008 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273844]  |
| 专题 | 药物发现与设计中心 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 | Halpert, JR |
| 作者单位 | 1.Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA 2.Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA 3.Chinese Acad Sci, Ctr Drug Discovery & Design, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai Inst Biol Sci,Grad Sch, Shanghai, Peoples R China 4.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, WH,Liu, H,Scott, EE,et al. Possible pathway(s) of testosterone egress from the active site of cytochrome P4502B1: A steered molecular dynamics simulation[J]. DRUG METABOLISM AND DISPOSITION,2005,33(7):910-919. |
| APA | Li, WH.,Liu, H.,Scott, EE.,Grater, F.,Halpert, JR.,...&Jiang, HL.(2005).Possible pathway(s) of testosterone egress from the active site of cytochrome P4502B1: A steered molecular dynamics simulation.DRUG METABOLISM AND DISPOSITION,33(7),910-919. |
| MLA | Li, WH,et al."Possible pathway(s) of testosterone egress from the active site of cytochrome P4502B1: A steered molecular dynamics simulation".DRUG METABOLISM AND DISPOSITION 33.7(2005):910-919. |
入库方式： OAI收割
来源：上海药物研究所
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