Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1
文献类型：期刊论文
| 作者 | Zhang, Ruihan1; Li, Xin2; Liang, Zhongjie3; Zhu, Kongkai1; Lu, Junyan1; Kong, Xiangqian1; Ouyang, Sisheng1; Li, Lin2; Zheng, Yujun George4; Luo, Cheng1,3
|
| 刊名 | PLOS ONE
 |
| 出版日期 | 2013-08-20 |
| 卷号 | 8期号:8 |
| ISSN号 | 1932-6203 |
| DOI | 10.1371/journal.pone.0072424 |
| 文献子类 | Article |
| 英文摘要 | Protein arginine methyltransferase 1 (PRMT1), the major arginine asymmetric dimethylation enzyme in mammals, is emerging as a potential drug target for cancer and cardiovascular disease. Understanding the catalytic mechanism of PRMT1 will facilitate inhibitor design. However, detailed mechanisms of the methyl transfer process and substrate deprotonation of PRMT1 remain unclear. In this study, we present a theoretical study on PRMT1 catalyzed arginine dimethylation by employing molecular dynamics (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) calculation. Ternary complex models, composed of PRMT1, peptide substrate, and S-adenosyl-methionine (AdoMet) as cofactor, were constructed and verified by 30-ns MD simulation. The snapshots selected from the MD trajectory were applied for the QM/MM calculation. The typical S(N)2-favored transition states of the first and second methyl transfers were identified from the potential energy profile. Deprotonation of substrate arginine occurs immediately after methyl transfer, and the carboxylate group of E144 acts as proton acceptor. Furthermore, natural bond orbital analysis and electrostatic potential calculation showed that E144 facilitates the charge redistribution during the reaction and reduces the energy barrier. In this study, we propose the detailed mechanism of PRMT1-catalyzed asymmetric dimethylation, which increases insight on the small-molecule effectors design, and enables further investigations into the physiological function of this family. |
| WOS关键词 | HISTONE LYSINE METHYLTRANSFERASE ; PRODUCT SPECIFICITY ; MOLECULAR-DYNAMICS ; SUBSTRATE PEPTIDES ; CRYSTAL-STRUCTURE ; METHYLATION ; PRMT1 ; QM/MM ; CONSTRAINTS ; INHIBITORS |
| 资助项目 | National High Technology Research and Development Program of China[2012AA020302] ; State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[91029704] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[21210003] ; Chinese Academy of Sciences[XDA01040305] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2013ZX09507-004] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000324527300085 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277502]  |
| 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 | Li, Lin |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China; 2.Shanghai Changzheng Hosp, Div Nephrol, Shanghai, Peoples R China; 3.Soochow Univ, Ctr Syst Biol, Suzhou, Jiangsu, Peoples R China; 4.Georgia State Univ, Dept Chem, Program Mol Basis Dis, Atlanta, GA 30303 USA |
| 推荐引用方式 GB/T 7714 | Zhang, Ruihan,Li, Xin,Liang, Zhongjie,et al. Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1[J]. PLOS ONE,2013,8(8). |
| APA | Zhang, Ruihan.,Li, Xin.,Liang, Zhongjie.,Zhu, Kongkai.,Lu, Junyan.,...&Luo, Cheng.(2013).Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1.PLOS ONE,8(8). |
| MLA | Zhang, Ruihan,et al."Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1".PLOS ONE 8.8(2013). |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。