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
- Journal of Oceanology and Limnology Vol. 38, Issue 6, Pages: 1891-1899(2020)
- 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：
- DOI：10.1007/s00343-019-9184-8
  CLC：
- Received：16 July 2019，
  
  Accepted：29 August 2019，
  
  Online First：12 November 2020，
  
  Published：2020-11
- Accepted：
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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：

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.

关键词

Keywords

references

P V Afonine , R W Grosse-Kunstleve , N Echols , J J Headd , N W Moriarty , M Mustyakimov , T C Terwilliger , A Urzhumtsev , P H Zwart , P D Adams . Towards automated crystallographic structure refinement with Phenix.refine . Acta Crystallographica Section D:Structural Biology , 2012 . 68 ( 4 ): 352 - 367 . DOI: 10.1107/S0907444912001308 http://doi.org/10.1107/S0907444912001308 .

A A Arvizu-Flores , E Aispuro-Hernandez , K D Garcia-Orozco , A Varela-Romero , E Valenzuela-Soto , E F VelazquezContreras , A Rojo-Domínguez , G Yepiz-Plascencia , F Maley , R R Sotelo-Mundo . Functional identity of the active sites of crustacean and viral thymidylate synthases . Comparative Biochemistry and Physiology Part C:Toxicology & Pharmacology , 2009 . 150 ( 3 ): 406 - 413 . DOI: 10.1016/j.cbpc.2009.06.008 http://doi.org/10.1016/j.cbpc.2009.06.008 .

C Aslanidis , P J de Jong . Ligation-independent cloning of PCR products (LIC-PCR) . Nucleic Acids Research , 1990 . 18 ( 20 ): 6 069 - 6 074 . DOI: 10.1093/nar/18.20.6069 http://doi.org/10.1093/nar/18.20.6069 .

D Cardinale , G Guaitoli , D Tondi , R Luciani , S Henrich , O M H SaloAhen , S Ferrari , G Marverti , D Guerrieri , A Ligabue , C Frassineti , C Pozzi , S Mangani , D Fessas , R Guerrini , G Ponterini , R C Wade , M P Costi . Proteinprotein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase . Proceedings of the National Academy of Sciences of the United States of America , 2011 . 108 ( 34 ): E542 - E549 . DOI: 10.1073/pnas.1104829108 http://doi.org/10.1073/pnas.1104829108 .

C W Carreras , D V Santi . The catalytic mechanism and structure of thymidylate synthase . Annual Review of Biochemistry , 1995 . 64 721 - 762 . DOI: 10.1146/annurev.bi.64.070195.003445 http://doi.org/10.1146/annurev.bi.64.070195.003445 .

D Chen , A Jansson , D Sim , A Larsson , P Nordlund . Structural analyses of human thymidylate synthase reveal a site that may control conformational switching between active and inactive states . The Journal of Biological Chemistry , 2017 . 292 ( 32 ): 13 449 - 13 458 . DOI: 10.1074/jbc.M117.787267 http://doi.org/10.1074/jbc.M117.787267 .

Y M Choi , H K Yeo , Y W Park , J Y Lee . Structural analysis of thymidylate synthase from Kaposi's sarcomaassociated herpesvirus with the anticancer drug raltitrexed . PLoS One , 2016 . 11 ( 12 ): e0168019 DOI: 10.1371/journal.pone.0168019 http://doi.org/10.1371/journal.pone.0168019 .

I W Davis , A Leaver-Fay , V B Chen , J N Block , G J Kapral , X Y Wang , L W Murray , III W B Arendall , J Snoeyink , J S Richardson , D C Richardson . MolProbity:allatom contacts and structure validation for proteins and nucleic acids . Nucleic Acids Research , 2007 . 35 ( S2 ): W375 - W383 . DOI: 10.1093/nar/gkm216 http://doi.org/10.1093/nar/gkm216 .

E de Clercq , J Balzarini , J Descamps , C F Bigge , C T C Chang , P Kalaritis , M P Mertes . Antiviral, antitumor, and thymidylate synthetase inhibition studies of 5-substituted styryl derivatives of 2'-deoxyuridine and their 5'-phosphates . Biochemical Pharmacology , 1981 . 30 ( 5 ): 495 - 502 . DOI: 10.1016/0006-2952(81)90635-3 http://doi.org/10.1016/0006-2952(81)90635-3 .

P Deschamps , S Réty , J Bareille , N Leulliot . Crystal structure of the active form of native human thymidylate synthase in the absence of bound substrates . Acta Crystallographica Section F:Structural Biology Communications , 2017 . 73 ( 6 ): 336 - 341 . DOI: 10.1107/S2053230X17007233 http://doi.org/10.1107/S2053230X17007233 .

A Dowierciał , P Wilk , W Rypniewski , W Rode , A Jarmuła . Crystal structure of mouse thymidylate synthase in tertiary complex with dUMP and raltitrexed reveals N-terminus architecture and two different active site conformations . Biomed Research International , 2014 . 2014 945803 DOI: 10.1155/2014/945803 http://doi.org/10.1155/2014/945803 .

P Emsley , B Lohkamp , W G Scott , K Cowtan . Features and development of Coot . Acta Crystallographica Section D:Structural Biology , 2010 . 66 ( 4 ): 486 - 501 . DOI: 10.1107/S0907444910007493 http://doi.org/10.1107/S0907444910007493 .

T W Flegel . Historic emergence, impact and current status of shrimp pathogens in Asia . Journal of Invertebrate Pathology , 2012 . 110 ( 2 ): 166 - 173 . DOI: 10.1016/j.jip.2012.03.004 http://doi.org/10.1016/j.jip.2012.03.004 .

Food and Agriculture Organization of the United Nations Globefish. 2018. Market Reports, http://www.fao.org/inaction/globefish http://www.fao.org/inaction/globefish .

L M Gibson , L L Lovelace , L Lebioda . The R163K mutant of human thymidylate synthase is stabilized in an active conformation:structural asymmetry and reactivity of cysteine 195 . Biochemistry , 2008 . 47 ( 16 ): 4 636 - 4 643 . DOI: 10.1021/bi7019386 http://doi.org/10.1021/bi7019386 .

L Holm , P Rosenström . Dali server:conservation mapping in 3D . Nucleic Acids Research , 2010 . 38 ( S2 ): W545 - W549 . DOI: 10.1093/nar/gkq366 http://doi.org/10.1093/nar/gkq366 .

Jackman A L. 1999. Antifolate Drugs in Cancer Therapy. Humana Press, Totowa NJ. 456p, https://doi.org/10.1007/978-1-59259-725-3 https://doi.org/10.1007/978-1-59259-725-3 .

D V Lightner , R M Redman , C R Pantoja , K F J Tang , B L Noble , P Schofield , L L Mohney , L M Nunan , S A Navarro . Historic emergence, impact and current status of shrimp pathogens in the Americas . Journal of Invertebrate Pathology , 2012 . 110 ( 2 ): 174 - 183 . DOI: 10.1016/j.jip.2012.03.006 http://doi.org/10.1016/j.jip.2012.03.006 .

A J McCoy , R W Grosse-Kunstleve , P D Adams , M D Winn , L C Storoni , R J Read . Phaser crystallographic software . Journal of Applied Crystallography , 2007 . 40 ( 4 ): 658 - 674 . DOI: 10.1107/S0021889807021206 http://doi.org/10.1107/S0021889807021206 .

K M Perry , E B Fauman , J S Finer-Moore , W R Montfort , G F Maley , F Maley , R M Stroud . Plastic adaptation toward mutations in proteins:structural comparison of thymidylate synthases . Proteins , 1990 . 8 ( 4 ): 315 - 333 . DOI: 10.1002/prot.340080406 http://doi.org/10.1002/prot.340080406 .

J Phan , S Koli , W Minor , R B Dunlap , S H Berger , L Lebioda . Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug . Biochemistry , 2001 . 40 ( 7 ): 1 897 - 1 902 . DOI: 10.1021/bi002413i http://doi.org/10.1021/bi002413i .

X Robert , P Gouet . Deciphering key features in protein structures with the new ENDscript server . Nucleic Acids Research , 2014 . 42 ( W1 ): W320 - W324 . DOI: 10.1093/nar/gku316 http://doi.org/10.1093/nar/gku316 .

Y M Rustum , A Harstrick , S Cao , U Vanhoefer , M B Yin , H Wilke , S Seeber . Thymidylate synthase inhibitors in cancer therapy:direct and indirect inhibitors . Journal of Clinical Oncology , 1997 . 15 ( 1 ): 389 - 400 . DOI: 10.1200/JCO.1997.15.1.389 http://doi.org/10.1200/JCO.1997.15.1.389 .

Y Satow , G H Cohen , E A Padlan , D R Davies . Phosphocholine binding immunoglobulin Fab McPC603:an X-ray diffraction study at 2 . 7 Å. Journal of Molecular Biology , 1986 . 190 ( 4 ): 593 - 604 . DOI: 10.1016/0022-2836(86)90245-7 http://doi.org/10.1016/0022-2836(86)90245-7 .

C A Schiffer , I J Clifton , V J Davisson , D V Santi , R M Stroud . Crystal structure of human thymidylate synthase:a structural mechanism for guiding substrates into the active site . Biochemistry , 1995 . 34 ( 50 ): 16 279 - 16 287 . DOI: 10.1021/bi00050a007 http://doi.org/10.1021/bi00050a007 .

O S Smart , T O Womack , C Flensburg , P Keller , W Paciorek , A Sharff , C Vonrhein , G Bricogne . Exploiting structure similarity in refinement:automated NCS and target-structure restraints in BUSTER . Acta Crystallographica Section D:Structural Biology , 2012 . 68 ( 4 ): 368 - 380 . DOI: 10.1107/S0907444911056058 http://doi.org/10.1107/S0907444911056058 .

T J Stout , D Tondi , M Rinaldi , D Barlocco , P Pecorari , D V Santi , I D Kuntz , R M Stroud , B K Shoichet , M P Costi . Structure-based design of inhibitors specific for bacterial thymidylate synthase . Biochemistry , 1999 . 38 ( 5 ): 1 607 - 1 617 . DOI: 10.1021/bi9815896 http://doi.org/10.1021/bi9815896 .

R M Stroud , J S Finer-Moore . Conformational dynamics along an enzymatic reaction pathway:thymidylate synthase, "the movie" . Biochemistry , 2003 . 42 ( 2 ): 239 - 247 . DOI: 10.1021/bi020598i http://doi.org/10.1021/bi020598i .

K Tamura , D Peterson , N Peterson , G Stecher , M Nei , S Kumar . MEGA5:molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods . Molecular Biology and Evolution , 2011 . 28 ( 10 ): 2 731 - 2 739 . DOI: 10.1093/molbev/msr121 http://doi.org/10.1093/molbev/msr121 .

C Vonrhein , C Flensburg , P Keller , A Sharff , O Smart , W Paciorek , T Womack , G Bricogne . Data processing and analysis with the autoPROC toolbox . Acta Crystallographica Section D:Structural Biology , 2011 . 67 ( 4 ): 293 - 302 . DOI: 10.1107/S0907444911007773 http://doi.org/10.1107/S0907444911007773 .

N Zaware , H Sharma , J Yang , R K V Devambatla , S F Queener , K S Anderson , A Gangjee . Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase for opportunistic infections . ACS Medicinal Chemistry Letters , 2013 . 4 ( 12 ): 1 148 - 1 151 . DOI: 10.1021/ml400208v http://doi.org/10.1021/ml400208v .

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