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Structural basis of malaria parasite lysyl-tRNA synthetase inhibition by cladosporin

  • Sameena Khan
  • Arvind Sharma
  • Hassan Belrhali
  • Manickam Yogavel
  • Amit SharmaEmail author
Article

Abstract

Malaria parasites inevitably develop drug resistance to anti-malarials over time. Hence the immediacy for discovering new chemical scaffolds to include in combination malaria drug therapy. The desirable attributes of new chemotherapeutic agents currently include activity against both liver and blood stage malaria parasites. One such recently discovered compound called cladosporin abrogates parasite growth via inhibition of Plasmodium falciparum lysyl-tRNA synthetase (PfKRS), an enzyme central to protein translation. Here, we present crystal structure of ternary PfKRS-lysine-cladosporin (PfKRS-K-C) complex that reveals cladosporin’s remarkable ability to mimic the natural substrate adenosine and thereby colonize PfKRS active site. The isocoumarin fragment of cladosporin sandwiches between critical adenine-recognizing residues while its pyran ring fits snugly in the ribose-recognizing cavity. PfKRS-K-C structure highlights ample space within PfKRS active site for further chemical derivatization of cladosporin. Such derivatives may be useful against additional human pathogens that retain high conservation in cladosporin chelating residues within their lysyl-tRNA synthetase.

Keywords

Cladosporin KRS Malaria X-ray crystal structure Inhibition 

Abbreviations

aaRSs

Aminoacyl-tRNA synthetases

AMP-PNP

Adenosine 5′-(β,γ-imido)triphosphate

ASU

Asymmetric unit

ATP

Adenosine triphosphate

CCDC

Cambridge crystallographic data centre

MST

Microscale thermophoresis

PDB

Protein data bank

PfKRS

Plasmodium falciparum lysyl-tRNA synthetase

PfKRS-K-C

PfKRS-lysine-cladosporin

RMSD

Root-mean-square-deviation

Notes

Acknowledgments

The authors thank Bart Staker, Seattle Structural Genomics Center for Infectious Disease (SSGCID), for supplying cladosporin. This research was supported by Department of Biotechnology, Government of India OSRP Grant PR6303 to AS.

References

  1. 1.
    Hoepfner D, McNamara CW, Lim CS, Studer C, Riedl R et al (2012) Cell Host Microbe 11:654–663PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Ibba M, Soll D (2000) Annu Rev Biochem 69:617–650PubMedCrossRefGoogle Scholar
  3. 3.
    Bhatt TK, Kapil C, Khan S, Jairajpuri MA, Sharma V et al (2009) BMC Genomics 10:644PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Bhatt TK, Khan S, Dwivedi VP, Banday MM, Sharma A et al (2011) Nat Commun 2:530PubMedCrossRefGoogle Scholar
  5. 5.
    Istvan ES, Dharia NV, Bopp SE, Gluzman I, Winzeler EA et al (2011) Proc Natl Acad Sci USA 108:1627–1632PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Jackson KE, Habib S, Frugier M, Hoen R, Khan S et al (2011) Trends Parasitol 27:467–476PubMedCrossRefGoogle Scholar
  7. 7.
    Khan S, Sharma A, Jamwal A, Sharma V, Pole AK et al (2011) Sci Rep 1:188PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Khan S, Garg A, Camacho N, Van Rooyen J, Kumar Pole A et al (2013) Acta Crystallogr D Biol Crystallogr 69:785–795PubMedCrossRefGoogle Scholar
  9. 9.
    Khan S, Garg A, Sharma A, Camacho N, Picchioni D et al (2013) PLoS One 8:e66224PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Azcarate IG, Marin-Garcia P, Camacho N, Perez-Benavente S, Puyet A et al (2013) Br J Pharmacol 169:645–658PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Hoen R, Novoa EM, Lopez A, Camacho N, Cubells L et al (2013) ChemBioChem 14:499–509PubMedCrossRefGoogle Scholar
  12. 12.
    Filisetti D, Theobald-Dietrich A, Mahmoudi N, Rudinger-Thirion J, Candolfi E et al (2013) J Biol Chem 288:36361–36371PubMedCrossRefGoogle Scholar
  13. 13.
    Koh CY, Kim JE, Napoli AJ, Verlinde CL, Fan E et al (2013) Mol Biochem Parasitol 189:26–32PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Mailu BM, Ramasamay G, Mudeppa DG, Li L, Lindner SE, Peterson MJ et al (2013) J Biol Chem 288:32539–32552PubMedCrossRefGoogle Scholar
  15. 15.
    Pham JS, Dawson KL, Jackson KE, Lim EE, Pasaje CF et al (2014) Int J Parasitol Drugs Drug Resist 4:1–13PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Cattel L, Grove JF, Shaw D (1973) J Chem Soc Perkin 1(21):2626–2629CrossRefGoogle Scholar
  17. 17.
    Jacyno JM, Harwood JS, Cutler HG, Lee MK (1993) J Nat Prod 56:1397–1401PubMedCrossRefGoogle Scholar
  18. 18.
    Zheng H, Zhao C, Fang B, Jing P, Yang J et al (2012) J Org Chem 77:5656–5663PubMedCrossRefGoogle Scholar
  19. 19.
    Guo M, Ignatov M, Musier-Forsyth K, Schimmel P, Yang XL (2008) Proc Natl Acad Sci USA 105:2331–2336PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Otwinowski Z, Minor W (1997) Methods Enzymol 276:307–326CrossRefGoogle Scholar
  21. 21.
    McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ (2007) J Appl Crystallogr 40:658–674PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW et al (2010) Acta Crystallogr D Biol Crystallogr 66:213–221PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Murshudov GN, Skubak P, Lebedev AA, Pannu NS, Steiner RA et al (2011) Acta Crystallogr D Biol Crystallogr 67:355–367PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P et al (2011) Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr 67:235–242PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Emsley P, Lohkamp B, Scott WG, Cowtan K (2010) Features and development of coot. Acta Crystallogr D Biol Crystallogr 66:486–501PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Chen VB, Arendall WB 3rd, Headd JJ, Keedy DA, Immormino RM et al (2010) Acta Crystallogr D Biol Crystallogr 66:12–21PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM et al (2004) J Comput Chem 25:1605–1612PubMedCrossRefGoogle Scholar
  28. 28.
    Wallace AC, Laskowski RA, Thornton JM (1995) Protein Eng 8:127–134PubMedCrossRefGoogle Scholar
  29. 29.
    Niesen FH, Berglund H, Vedadi M (2007) Nat Protoc 2:2212–2221PubMedCrossRefGoogle Scholar
  30. 30.
    Wienken CJ, Baaske P, Rothbauer U, Braun D, Duhr S (2010) Nat Commun 1:100PubMedCrossRefGoogle Scholar
  31. 31.
    Le Guilloux V, Schmidtke P, Tuffery P (2009) BMC Bioinform 10:168CrossRefGoogle Scholar
  32. 32.
    Doerig C, Baker D, Billker O, Blackman MJ, Chitnis C et al (2009) Parasite 16:169–182PubMedCrossRefGoogle Scholar
  33. 33.
    Hora R, Bridges DJ, Craig A, Sharma A (2009) J Biol Chem 284:6260–6269PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Sharma A, Yogavel M, Akhouri RR, Gill J, Sharma A (2008) J Biol Chem 283:24077–24088PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Gill J, Yogavel M, Kumar A, Belrhali H, Jain SK et al (2009) J Biol Chem 284:10076–10087PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Sameena Khan
    • 1
  • Arvind Sharma
    • 1
  • Hassan Belrhali
    • 2
  • Manickam Yogavel
    • 1
  • Amit Sharma
    • 1
    Email author
  1. 1.Structural and Computational Biology GroupInternational Centre for Genetic Engineering and Biotechnology (ICGEB)New DelhiIndia
  2. 2.European Molecular Biology LaboratoryGrenobleFrance

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