Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase
文献类型：期刊论文
| 作者 | Chen, Huayou1,2,3; Tian, Rui1; Ni, Zhong1; Zhang, Zhongge2; Chen, Hongzhang3 ; Guo, Qi1; Saier, Milton H., Jr.2
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| 刊名 | PROTEIN JOURNAL
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| 出版日期 | 2014-12-01 |
| 卷号 | 33期号:6页码:503-511 |
| 关键词 | MGL MD simulations Nudged elastic band Conformational transition pathway |
| ISSN号 | 1572-3887 |
| 其他题名 | Protein J. |
| 中文摘要 | Human monoacylglycerol lipase (MGL) catalyzes the hydrolysis of 2-arachidonoylglycerol to arachidonic and glycerol, which plays a pivotal role in the normal biological processes of brain. Co-crystal structure of the MGL in complex with its inhibitor, compound 1, shows that the helix alpha 4 undergoes large-scale conformational changes in response to the compound 1 binding compared to the apo MGL. However, the detailed conformational transition pathway of the helix alpha 4 in the inhibitor binding process of MGL has remained unclear. Here, conventional molecular dynamics (MD) and nudged elastic band (NEB) simulations were performed to explore the conformational transition pathway of the helix alpha 4. Conventional MD simulations unveiled that the compound 1 induced the closed conformation of the active site of MGL, reduced the conformational flexibility of the helix alpha 4, and elicited the large-scale conformational rearrangement of the helix alpha 4, leading to the complete folding of the helix alpha 4. Moreover, NEB simulations revealed that the conformational transition pathway of helix alpha 4 underwent an almost 180A degrees counter-clockwise rotation of the helix alpha 4. Our computational results advance the structural and mechanistic understanding of the inhibitory mechanism. |
| 英文摘要 | Human monoacylglycerol lipase (MGL) catalyzes the hydrolysis of 2-arachidonoylglycerol to arachidonic and glycerol, which plays a pivotal role in the normal biological processes of brain. Co-crystal structure of the MGL in complex with its inhibitor, compound 1, shows that the helix alpha 4 undergoes large-scale conformational changes in response to the compound 1 binding compared to the apo MGL. However, the detailed conformational transition pathway of the helix alpha 4 in the inhibitor binding process of MGL has remained unclear. Here, conventional molecular dynamics (MD) and nudged elastic band (NEB) simulations were performed to explore the conformational transition pathway of the helix alpha 4. Conventional MD simulations unveiled that the compound 1 induced the closed conformation of the active site of MGL, reduced the conformational flexibility of the helix alpha 4, and elicited the large-scale conformational rearrangement of the helix alpha 4, leading to the complete folding of the helix alpha 4. Moreover, NEB simulations revealed that the conformational transition pathway of helix alpha 4 underwent an almost 180A degrees counter-clockwise rotation of the helix alpha 4. Our computational results advance the structural and mechanistic understanding of the inhibitory mechanism. |
| WOS标题词 | Science & Technology ; Life Sciences & Biomedicine |
| 类目[WOS] | Biochemistry & Molecular Biology |
| 研究领域[WOS] | Biochemistry & Molecular Biology |
| 关键词[WOS] | MOLECULAR-DYNAMICS SIMULATION ; MONOGLYCERIDE LIPASE ; CANNABINOID RECEPTOR ; 2-ARACHIDONOYLGLYCEROL ; INACTIVATION ; HYDROLYSIS ; ENZYME ; ANANDAMIDE ; GSK3-BETA ; MECHANISM |
| 收录类别 | SCI |
| 原文出处 | |
| 语种 | 英语 |
| WOS记录号 | WOS:000345437000001 |
| 公开日期 | 2015-04-01 |
| 源URL | [http://ir.ipe.ac.cn/handle/122111/11707]  |
| 专题 | 过程工程研究所_研究所（批量导入） |
| 作者单位 | 1.Jiangsu Univ, Inst Life Sci, Zhenjiang 212013, Peoples R China 2.Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA 3.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing 10090, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Huayou,Tian, Rui,Ni, Zhong,et al. Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase[J]. PROTEIN JOURNAL,2014,33(6):503-511. |
| APA | Chen, Huayou.,Tian, Rui.,Ni, Zhong.,Zhang, Zhongge.,Chen, Hongzhang.,...&Saier, Milton H., Jr..(2014).Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase.PROTEIN JOURNAL,33(6),503-511. |
| MLA | Chen, Huayou,et al."Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase".PROTEIN JOURNAL 33.6(2014):503-511. |
入库方式： OAI收割
来源：过程工程研究所
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