Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed

Changshui LIU; Kun ZANG; Shihao LI; Fuhua LI; Qingjun MA

doi:10.1007/s00343-019-9184-8

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Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed

Biology | Updated：2023-04-27

- Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed
- Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed
- 海洋湖沼学报（英文） 2020年38卷第6期页码：1891-1899
- Affiliations：
  
  1.Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China
  2.Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266000, China
  3.University of Chinese Academy of Sciences, Beijing 100049, China
  4.Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China
- Author bio：
  
  MA Qingjun, qma@qdio.ac.cn
- Funds：
  
  the National Natural Science Foundation of China(31572660);the National Natural Science Foundation of China(31872600);the "1000 Talents Program";the Qingdao Innovation Leadership Project(18-1-2-12-zhc);© Chinese Society for Oceanology and Limnology, Science Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
- DOI：10.1007/s00343-019-9184-8
  中图分类号：
- 收稿：2019-07-16，
  
  录用：2019-8-29，
  
  网络首发：2020-11-12，
  
  纸质出版：2020-11
- Accepted：
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Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed[J]. 海洋湖沼学报（英文）, 2020,38(6):1891-1899.

Changshui LIU, Kun ZANG, Shihao LI, et al. Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed[J]. Journal of Oceanology and Limnology, 2020, 38(6): 1891-1899.
Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed[J]. 海洋湖沼学报（英文）, 2020,38(6):1891-1899. DOI： 10.1007/s00343-019-9184-8.

Changshui LIU, Kun ZANG, Shihao LI, et al. Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed[J]. Journal of Oceanology and Limnology, 2020, 38(6): 1891-1899. DOI： 10.1007/s00343-019-9184-8.

摘要

Abstract

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 Å

1.54 Å

and 1.56 Å 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 Sγ 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.

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Keywords

references

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