Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1

doi:10.1371/journal.pone.0072424

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1
	Zhang, Ruihan 1; Li, Xin 2; Liang, Zhongjie 3; Zhu, Kongkai 1; Lu, Junyan 1; Kong, Xiangqian 1; Ouyang, Sisheng 1; Li, Lin 2; Zheng, Yujun George 4; Luo, Cheng1,3
刊名	PLOS ONE
	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.
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关键词	HISTONE LYSINE METHYLTRANSFERASE ; PRODUCT SPECIFICITY ; MOLECULAR-DYNAMICS ; SUBSTRATE PEPTIDES ; CRYSTAL-STRUCTURE ; METHYLATION ; PRMT1 ; QM/MM ; CONSTRAINTS ; INHIBITORS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000324527300085
内容类型	期刊论文
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).