Catalytic Mechanism Investigation of Lysine-Specific Demethylase 1 (LSD1): A Computational Study

doi:10.1371/journal.pone.0025444

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	Catalytic Mechanism Investigation of Lysine-Specific Demethylase 1 (LSD1): A Computational Study
	Kong, Xiangqian 1; Ouyang, Sisheng 1; Liang, Zhongjie 1; Lu, Junyan 1; Chen, Liang 1; Shen, Bairong 2; Li, Donghai 3; Zheng, Mingyue1 ; Li, Keqin Kathy 4; Luo, Cheng1,2
刊名	PLOS ONE
	2011-09-30
卷号	6 期号:9
ISSN号	1932-6203
DOI	10.1371/journal.pone.0025444
文献子类	Article
英文摘要	Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is a flavin-dependent amine oxidase which specifically demethylates mono-or dimethylated H3K4 and H3K9 via a redox process. It participates in a broad spectrum of biological processes and is of high importance in cell proliferation, adipogenesis, spermatogenesis, chromosome segregation and embryonic development. To date, as a potential drug target for discovering anti-tumor drugs, the medical significance of LSD1 has been greatly appreciated. However, the catalytic mechanism for the rate-limiting reductive half-reaction in demethylation remains controversial. By employing a combined computational approach including molecular modeling, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, the catalytic mechanism of dimethylated H3K4 demethylation by LSD1 was characterized in details. The three-dimensional (3D) model of the complex was composed of LSD1, CoREST, and histone substrate. A 30-ns MD simulation of the model highlights the pivotal role of the conserved Tyr761 and lysine-water-flavin motif in properly orienting flavin adenine dinucleotide (FAD) with respect to substrate. The synergy of the two factors effectively stabilizes the catalytic environment and facilitated the demethylation reaction. On the basis of the reasonable consistence between simulation results and available mutagenesis data, QM/MM strategy was further employed to probe the catalytic mechanism of the reductive half-reaction in demethylation. The characteristics of the demethylation pathway determined by the potential energy surface and charge distribution analysis indicates that this reaction belongs to the direct hydride transfer mechanism. Our study provides insights into the LSD1 mechanism of reductive half-reaction in demethylation and has important implications for the discovery of regulators against LSD1 enzymes.
资助项目	State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[20972174] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[31000323] ; National Natural Science Foundation of China[91029704] ; Shanghai Committee of Science and Technology[10410703900] ; Specialized Research Fund for the Doctoral Program of Higher Education of China[20100091120023] ; Chinese Academy of Sciences[XDA01040305]
WOS关键词	AMINO-ACID OXIDASE ; N-METHYLTRYPTOPHAN OXIDASE ; MOLECULAR-ORBITAL METHOD ; MONOAMINE-OXIDASE ; POLYAMINE OXIDASE ; HISTONE DEMETHYLASE ; CRYSTAL-STRUCTURE ; GEOMETRY OPTIMIZATION ; STRUCTURAL BASIS ; PH-DEPENDENCE
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000295941300031
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278396]
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	Kong, Xiangqian
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 200031, Peoples R China; 2.Soochow Univ, Ctr Syst Biol, Suzhou, Jiangsu, Peoples R China; 3.Nanjing Univ, Sch Life Sci, Jiangsu Diabet Res Ctr, State Key Lab Pharmaceut Biotechnol, Nanjing 210008, Peoples R China; 4.Shanghai Jiao Tong Univ, Sch Med, Rui Jin Hosp, State Key Lab Med Genom,Shanghai Inst Hematol, Shanghai 200030, Peoples R China; 5.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
推荐引用方式 GB/T 7714	Kong, Xiangqian,Ouyang, Sisheng,Liang, Zhongjie,et al. Catalytic Mechanism Investigation of Lysine-Specific Demethylase 1 (LSD1): A Computational Study[J]. PLOS ONE,2011,6(9).
APA	Kong, Xiangqian.,Ouyang, Sisheng.,Liang, Zhongjie.,Lu, Junyan.,Chen, Liang.,...&Jiang, Hualiang.(2011).Catalytic Mechanism Investigation of Lysine-Specific Demethylase 1 (LSD1): A Computational Study.PLOS ONE,6(9).
MLA	Kong, Xiangqian,et al."Catalytic Mechanism Investigation of Lysine-Specific Demethylase 1 (LSD1): A Computational Study".PLOS ONE 6.9(2011).