Exploring the RING-Catalyzed Ubiquitin Transfer Mechanism by MD and QM/MM Calculations
文献类型：期刊论文
| 作者 | Zhen, Yunmei1,2; Qin, Guangrong2; Luo, Cheng2 ; Jiang, Hualiang2; Yu, Kunqian2; Chen, Guanghui3
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| 刊名 | PLOS ONE
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| 出版日期 | 2014-07-08 |
| 卷号 | 9期号:7 |
| ISSN号 | 1932-6203 |
| DOI | 10.1371/journal.pone.0101663 |
| 文献子类 | Article |
| 英文摘要 | Ubiquitylation is a universal mechanism for controlling cellular functions. A large family of ubiquitin E3 ligases (E3) mediates Ubiquitin (Ub) modification. To facilitate Ub transfer, RING E3 ligases bind both the substrate and ubiquitin E2 conjugating enzyme (E2) linked to Ub via a thioester bond to form a catalytic complex. The mechanism of Ub transfer catalyzed by RING E3 remains elusive. By employing a combined computational approach including molecular modeling, molecular dynamics (MD) simulations, and quantum mechanics/molecular mechanics (QM/MM) calculations, we characterized this catalytic mechanism in detail. The three-dimensional model of dimeric RING E3 ligase RNF4 RING, E2 ligase UbcH5A, Ub and the substrate SUMO2 shows close contact between the substrate and Ub transfer catalytic center. Deprotonation of the substrate lysine by D117 on UbcH5A occurs with almost no energy barrier as calculated by MD and QM/MM calculations. Then, the side chain of the activated lysine gets close to the thioester bond via a conformation change. The Ub transfer pathway begins with a nucleophilic addition that forms an oxyanion intermediate of a 4.23 kcal/mol energy barrier followed by nucleophilic elimination, resulting in a Ub modified substrate by a 5.65 kcal/mol energy barrier. These results provide insight into the mechanism of RING-catalyzed Ub transfer guiding the discovery of Ub system inhibitors. |
| WOS关键词 | E3 LIGASE ACTIVITY ; MOLECULAR-DYNAMICS ; DNA-DAMAGE ; MASS-SPECTROMETRY ; DRUG TARGETS ; RESP MODEL ; SUMO ; RNF4 ; COMPLEX ; CONJUGATION |
| 资助项目 | National High Technology Research and Development Program of China (863 Program)[2012AA020301] ; National High Technology Research and Development Program of China (863 Program)[2012AA01A305] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[21210003] ; Chinese Academy of Sciences[KSZD-EW-L09-4] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000339242700050 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276989]  |
| 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 | Yu, Kunqian |
| 作者单位 | 1.Shantou Univ, Dept Biol, Shantou, Guangdong, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 200031, Peoples R China; 3.Shantou Univ, Dept Chem, Shantou, Guangdong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhen, Yunmei,Qin, Guangrong,Luo, Cheng,et al. Exploring the RING-Catalyzed Ubiquitin Transfer Mechanism by MD and QM/MM Calculations[J]. PLOS ONE,2014,9(7). |
| APA | Zhen, Yunmei,Qin, Guangrong,Luo, Cheng,Jiang, Hualiang,Yu, Kunqian,&Chen, Guanghui.(2014).Exploring the RING-Catalyzed Ubiquitin Transfer Mechanism by MD and QM/MM Calculations.PLOS ONE,9(7). |
| MLA | Zhen, Yunmei,et al."Exploring the RING-Catalyzed Ubiquitin Transfer Mechanism by MD and QM/MM Calculations".PLOS ONE 9.7(2014). |
入库方式： OAI收割
来源：上海药物研究所
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