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

  • Changshui Liu
  • Kun Zang
  • Shihao Li
  • Fuhua Li
  • Qingjun MaEmail author
Article

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.

Keywords

thymidylate synthase (TS) closed conformation deoxyuridine monophosphate (dUMP) thymidine monophosphate (TMP) raltitrexed Litopenaeus vannamei 

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Notes

Acknowledgment

We thank the staffs from the BL17U1 and BL19U1 beamline stations at SSRF for assistance during data collection.

Supplementary material

343_2019_9184_MOESM1_ESM.pdf (1.4 mb)
Supplementary material, approximately 1.4 MB.

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Copyright information

© Chinese Society for Oceanology and Limnology, Science Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Changshui Liu
    • 1
    • 2
  • Kun Zang
    • 1
    • 2
    • 3
  • Shihao Li
    • 1
    • 2
    • 3
    • 4
  • Fuhua Li
    • 1
    • 2
    • 3
    • 4
  • Qingjun Ma
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Key Laboratory of Experimental Marine Biology, Institute of OceanologyChinese Academy of SciencesQingdaoChina
  2. 2.Laboratory for Marine Biology and BiotechnologyQingdao National Laboratory for Marine Science and TechnologyQingdaoChina
  3. 3.University of Chinese Academy of SciencesBeijingChina
  4. 4.Center for Ocean Mega-ScienceChinese Academy of SciencesQingdaoChina

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