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Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed
Liu Changshui1,2; Zang Kun1,2,3; Li Shihao1,2,3,4; Li Fuhua1,2,3,4; Ma Qingiun1,2,3,4
2020-02-15
发表期刊JOURNAL OF OCEANOLOGY AND LIMNOLOGY
ISSN2096-5508
页码9
通讯作者Ma Qingiun(qma@qdio.ac.cn)
摘要Thymidylate synthase (TS) is a key enzyme in the de novo biosynthesis of thymidine monophosphate, serving as a well-known drug target in chemotherapy against cancers and infectious diseases. Additional to its clinical value, TS is supposed to be a promising drug target in aquatic-disease control. To facilitate designing pathogen-specific TS inhibitors for shrimp-disease control, we report the crystal structures of TS from Litopenaeus vannamei (LvTS) in the apo form, LvTS-dUMP complex and LvTS-dUMP-raltitrexed complex at 2.27 A, 1.54 A, and 1.56 A resolution, respectively. LvTS shares a similar fold with known TSs, existing as a dimer in the crystal. The apo LvTS and LvTS-dUMP take an open conformation, and raltitrexed binding induces structural changes into a closed conformation in LvTS-dUMP-raltitrexed. Compared to those in other known TS-dUMP-raltitrexed complexes with the closed conformation, the C-terminal loop in LvTS-dUMP-raltitrexed shifts its position away from the bound raltitrexed; the distance between C6 of dUMP and S gamma of the catalytic cysteine is obviously longer than that in the known TS structures with closed conformations, resembling that in the TS structures with open conformations. Other species-specific interactions with dUMP and raltitrexed are also observed. Therefore, LvTS-dUMP-raltitrexed adopts a loosely closed conformation with structural features intermediate between the closed and the open conformations that were reported in other TSs. Our study provides the first crustcean TS structure, and reveals species-specific interactions between TSs and the ligands, which would facilitate designing pathogen-specific TS inhibitors for shrimp-disease control.
关键词thymidylate synthase (TS) closed conformation deoxyuridine monophosphate (dUMP) thymidine monophosphate (TMP) raltitrexed Litopenaeus vannamei
DOI10.1007/s00343-019-9184-8
收录类别SCI
语种英语
资助项目National Natural Science Foundation of China[31572660] ; National Natural Science Foundation of China[31872600] ; 1000 Talents Program ; Qingdao Innovation Leadership Project[18-1-2-12-zhc]
WOS研究方向Marine & Freshwater Biology ; Oceanography
WOS类目Limnology ; Oceanography
WOS记录号WOS:000516140400007
出版者SCIENCE PRESS
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.qdio.ac.cn/handle/337002/165539
专题实验海洋生物学重点实验室
通讯作者Ma Qingiun
作者单位1.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao 266071, Peoples R China
2.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao 266000, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Ctr Ocean Megasci, Qingdao 266071, Peoples R China
第一作者单位实验海洋生物学重点实验室
通讯作者单位实验海洋生物学重点实验室;  中国科学院海洋大科学研究中心
推荐引用方式
GB/T 7714
Liu Changshui,Zang Kun,Li Shihao,et al. Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed[J]. JOURNAL OF OCEANOLOGY AND LIMNOLOGY,2020:9.
APA Liu Changshui,Zang Kun,Li Shihao,Li Fuhua,&Ma Qingiun.(2020).Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed.JOURNAL OF OCEANOLOGY AND LIMNOLOGY,9.
MLA Liu Changshui,et al."Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed".JOURNAL OF OCEANOLOGY AND LIMNOLOGY (2020):9.
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