Molecular Mechanism underlying PRMT1 Dimerization for SAM Binding and Methylase Activity

doi:10.1021/acs.jcim.5b00454

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	Molecular Mechanism underlying PRMT1 Dimerization for SAM Binding and Methylase Activity
	Zhou, Ran 1,2; Xie, Yiqian 2; Hu, Hao 3; Hu, Guang 1; Patel, Viral Sanjay 3; Zhang, Jin 4; Yu, Kunqian2 ; Huang, Yiran 4; Jiang, Hualiang2 ; Liang, Zhongjie 1
刊名	JOURNAL OF CHEMICAL INFORMATION AND MODELING
	2015-12
卷号	55 期号:12 页码:2623-2632
ISSN号	1549-9596
DOI	10.1021/acs.jcim.5b00454
文献子类	Article
英文摘要	Protein arginine methyltransferases (PRMTs) catalyze the posttranslational methylation of arginine, which is important in a range of biological processes, including epigenetic regulation, signal transduction, and cancer progression. Although previous studies of PRMT1 mutants suggest that the dimerization arm and the N-terminal region of PRMT1 are important for activity, the contributions of these regions to the structural architecture of the protein and its catalytic methylation activity remain elusive. Molecular dynamics (MD) simulations performed in this study showed that both the dimerization arm and the N-terminal region undergo conformational changes upon dimerization. Because a correlation was found between the two regions despite their physical distance, an allosteric pathway mechanism was proposed based on a network topological analysis. The mutation of residues along the allosteric pathways markedly reduced the methylation activity of PRMT1, which may be attributable to the destruction of dimer formation and accordingly reduced S-adenosyl-(L)-methionine (SAM) binding. This study provides the first demonstration of the use of a combination of MD simulations, network topological analysis, and biochemical assays for the exploration of allosteric regulation upon PRMT1 dimerization. These findings illuminate the results of mechanistic studies of PRMT1, which have revealed that dimer formation facilitates SAM binding and catalytic methylation, and provided direction for further allosteric studies of the PRMT family.
资助项目	Ministry of Science and Technology of China[2015CB910304] ; Hi-Tech Research and Development Program of China[2012AA020301] ; Hi-Tech Research and Development Program of China[2012AA01A305] ; Hi-Tech Research and Development Program of China[2012AA020302] ; National Natural Science Foundation of China[81472378] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[21203131] ; National Natural Science Foundation of China[81302700] ; NIH[R01GM086717]
WOS关键词	PROTEIN-ARGININE METHYLTRANSFERASE ; BIOLOGICAL EVALUATION ; DYNAMICS SIMULATIONS ; SELECTIVE INHIBITORS ; NETWORK ANALYSIS ; FORCE-FIELD ; COACTIVATOR-ASSOCIATED-ARGININE-METHYLTRANSFERASE-1 ; DIMETHYLATION ; INSIGHTS ; PROGRAM
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000367560200014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276296]
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	Liang, Zhongjie
作者单位	1.Soochow Univ, Ctr Syst Biol, Suzhou 215006, Jiangsu, Peoples R China; 2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Univ Georgia, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA; 4.Shanghai Jiao Tong Univ, Dept Urol, Renji Hosp, Sch Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhou, Ran,Xie, Yiqian,Hu, Hao,et al. Molecular Mechanism underlying PRMT1 Dimerization for SAM Binding and Methylase Activity[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2015,55(12):2623-2632.
APA	Zhou, Ran.,Xie, Yiqian.,Hu, Hao.,Hu, Guang.,Patel, Viral Sanjay.,...&Luo, Cheng.(2015).Molecular Mechanism underlying PRMT1 Dimerization for SAM Binding and Methylase Activity.JOURNAL OF CHEMICAL INFORMATION AND MODELING,55(12),2623-2632.
MLA	Zhou, Ran,et al."Molecular Mechanism underlying PRMT1 Dimerization for SAM Binding and Methylase Activity".JOURNAL OF CHEMICAL INFORMATION AND MODELING 55.12(2015):2623-2632.