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

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


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.


Cladosporin KRS Malaria X-ray crystal structure Inhibition 



Aminoacyl-tRNA synthetases


Adenosine 5′-(β,γ-imido)triphosphate


Asymmetric unit


Adenosine triphosphate


Cambridge crystallographic data centre


Microscale thermophoresis


Protein data bank


Plasmodium falciparum lysyl-tRNA synthetase







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.


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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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