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Biochemical Studies and Molecular Dynamic Simulations Reveal the Molecular Basis of Conformational Changes in DNA Methyltransferase-1

文献类型：期刊论文

作者Ye, Fei5,6; Kong, Xiangqian4; Zhang, Hao5; Liu, Yan5; Shao, Zhiyuan5; Jin, Jia6; Cai, Yi4; Zhang, Rukang5; Li, Linjuan5; Zhang, Uang W.4
刊名ACS CHEMICAL BIOLOGY
出版日期2018-03
卷号13期号:3页码:772-781
ISSN号1554-8929
DOI10.1021/acschembio.7b00890
文献子类Article
英文摘要DNA methyltransferase-1 (DNMT1) plays a crucial role in the maintenance of genomic methylation patterns. The crystal structure of DNMT1 was determined in two different states in which the helix that follows the catalytic loop was either kinked (designated helix-kinked) or well folded (designated helix-straight state). Here, we show that the proper structural transition between these two states is required for DNMT1 activity. The mutations of N1248A and R1279D, which did not affect interactions between DNMT1 and substrates or cofactors, allosterically reduced enzymatic activities in vitro by decreasing k(cat)/K-m for AdoMet. The crystallographic data combined with molecular dynamic (MD) simulations indicated that the N1248A and R1279D mutants bias the catalytic helix to either the kinked or straight conformation. In addition, genetic complementation assays for the two mutants suggested that disturbing the conformational transition reduced DNMT1 activity in cells, which could act additively with existing DNMT inhibitors to decrease DNA methylation. Collectively, our studies provide molecular insights into conformational changes of the catalytic helix, which is essential for DNMT1 catalytic activity, and thus aid in better understanding the relationship between DNMT1 dynamic switching and enzymatic activity.
WOS关键词HUMAN CANCER-CELLS ; ADENOSYL-L-METHIONINE ; DE-NOVO METHYLATION ; CYTOSINE-5 METHYLTRANSFERASES ; CRYSTAL-STRUCTURE ; DNMT1 ; GENE ; INACTIVATION ; DISRUPTION ; PATTERNS
资助项目Computer Network Information Center, Chinese Academy of Sciences[00000000] ; Tianjin Supercomputing Center[00000000] ; National Key R&D Program of China[2017YFB0202600] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81703415] ; National Natural Science Foundation of China[81430084] ; CAS Strategic Priority Research Program[XDA12020304] ; CAS Strategic Priority Research Program[XDA12020353] ; Zhejiang Province Natural Science Foundation[LY18H300008] ; Shanghai Sailing Program[17YF1423100] ; National Institutes of Environmental Health Sciences (NIEHS)[RO1 ES011858] ; Hodson Trust[00000000] ; China Postdoctoral Science Foundation[2016M601676] ; National Key Scientific Instrument & Equipment Development Program of China[2012YQ03026010]
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:000428003000035
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/279866]  
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
天然药物化学研究室
通讯作者Chen, Shijie; Baylin, Stephen B.; Luo, Cheng
作者单位1.Shanghai ChemPartner Co LTD, Bldg 5,998 Halei Rd,Zhangjiang Hi Tech Pk, Shanghai 201203, Peoples R China;
2.Shanghai Univ Tradit Chinese Med, Sch Pharm, 1200 Cailun Rd, Shanghai 201203, Peoples R China
3.China Novartis Inst BioMed Res, Shanghai 201203, Peoples R China;
4.Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Oncol, Baltimore, MD 21287 USA;
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr,CAS Key Lab Receptor, Shanghai 201203, Peoples R China;
6.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Peoples R China;
推荐引用方式
GB/T 7714		 Ye, Fei,Kong, Xiangqian,Zhang, Hao,et al. Biochemical Studies and Molecular Dynamic Simulations Reveal the Molecular Basis of Conformational Changes in DNA Methyltransferase-1[J]. ACS CHEMICAL BIOLOGY,2018,13(3):772-781.
APA Ye, Fei.,Kong, Xiangqian.,Zhang, Hao.,Liu, Yan.,Shao, Zhiyuan.,...&Luo, Cheng.(2018).Biochemical Studies and Molecular Dynamic Simulations Reveal the Molecular Basis of Conformational Changes in DNA Methyltransferase-1.ACS CHEMICAL BIOLOGY,13(3),772-781.
MLA Ye, Fei,et al."Biochemical Studies and Molecular Dynamic Simulations Reveal the Molecular Basis of Conformational Changes in DNA Methyltransferase-1".ACS CHEMICAL BIOLOGY 13.3(2018):772-781.

入库方式： OAI收割

来源：上海药物研究所

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