A computational investigation on the substrate preference of ten-eleven-translocation 2 (TET2)

doi:10.1039/c5cp07266b

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

	A computational investigation on the substrate preference of ten-eleven-translocation 2 (TET2)
	Lu, Junyan 2; Hu, Lulu 3,4; Cheng, Jingdong 3; Fang, Dong 1,5; Wang, Chen 2; Yu, Kunqian2 ; Jiang, Hualiang2 ; Cui, Qiang 1,5; Xu, Yanhui 3,4; Luo, Cheng2
刊名	PHYSICAL CHEMISTRY CHEMICAL PHYSICS
	2016-02-14
卷号	18 期号:6 页码:4728-4738
ISSN号	1463-9076
DOI	10.1039/c5cp07266b
文献子类	Article
英文摘要	TET proteins iteratively convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) in a Fe(II)/alpha-ketoglutarate-dependent manner. Our previous biochemical studies revealed that TET proteins are more active on 5mC than on 5hmC and 5fC. However, the source of the substrate preference of TET proteins still remains largely elusive. Here, we investigated the substrate binding and catalytic mechanisms of oxidation reactions mediated by TET2 on different substrates through computational approaches. In accordance with previous experimental reports, our computational results suggest that TET2 can bind to different substrates with comparable binding affinities and the hydrogen abstraction step in the catalytic cycle acts as the rate-limiting step. Further structural characterization of the intermediate structures revealed that the 5-substitution groups on 5hmC and 5fC adopt an unfavorable orientation for hydrogen abstraction, which leads to a higher energy barrier for 5hmC and 5fC (compared to 5mC) and thus a lower catalytic efficiency. In summary, our mechanical insights demonstrate that substrate preference is the intrinsic property of TET proteins and our theoretical calculation results can guide further dry-lab or wet-lab studies on the catalytic mechanism of TET proteins as well as other Fe(II)/alpha-ketoglutarate (KG)-dependent dioxygenases.
资助项目	National Basic Research Program of China[2015CB910304] ; National Basic Research Program of China[2011CB965300] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2014ZX09507-002] ; National Natural Science Foundation of China[U1432242] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[31425008] ; National Natural Science Foundation of China[91419301] ; National Natural Science Foundation of China[21210003] ; Basic Research Project of Shanghai Science and Technology Commission[12JC1402700] ; Program of Shanghai Subject Chief Scientist[14XD1400500] ; Hi-Tech Research and Development Program of China[2012AA020302] ; Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505] ; Shanghai Municipal Education Commission[11SG06] ; Shanghai Education Development Foundation[11SG06]
WOS关键词	AMBER FORCE-FIELD ; EMBRYONIC STEM-CELLS ; MEDIATED FORMATION ; DNA DEMETHYLATION ; MAMMALIAN DNA ; 5-HYDROXYMETHYLCYTOSINE ; ALKB ; METHYLATION ; PROTEINS ; REPAIR
WOS研究方向	Chemistry ; Physics
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000369509100055
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276145]
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	Xu, Yanhui; Luo, Cheng
作者单位	1.Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 3.Fudan Univ, Shanghai Med Coll, Shanghai Canc Ctr, Inst Biomed Sci, Shanghai 200032, Peoples R China; 4.Fudan Univ, Sch Life Sci, Collaborat Innovat Ctr Genet & Dev, State Key Lab Genet Engn, Shanghai 200433, Peoples R China; 5.Univ Wisconsin, Inst Theoret Chem, 1101 Univ Ave, Madison, WI 53706 USA
推荐引用方式 GB/T 7714	Lu, Junyan,Hu, Lulu,Cheng, Jingdong,et al. A computational investigation on the substrate preference of ten-eleven-translocation 2 (TET2)[J]. PHYSICAL CHEMISTRY CHEMICAL PHYSICS,2016,18(6):4728-4738.
APA	Lu, Junyan.,Hu, Lulu.,Cheng, Jingdong.,Fang, Dong.,Wang, Chen.,...&Luo, Cheng.(2016).A computational investigation on the substrate preference of ten-eleven-translocation 2 (TET2).PHYSICAL CHEMISTRY CHEMICAL PHYSICS,18(6),4728-4738.
MLA	Lu, Junyan,et al."A computational investigation on the substrate preference of ten-eleven-translocation 2 (TET2)".PHYSICAL CHEMISTRY CHEMICAL PHYSICS 18.6(2016):4728-4738.