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

  • Published:
Journal of Structural and Functional Genomics

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.

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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

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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.

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Authors and Affiliations

  1. Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, 110067, India

    Sameena Khan, Arvind Sharma, Manickam Yogavel & Amit Sharma

  2. European Molecular Biology Laboratory, 6 Rue Jules Horowitz, BP 181, 38042, Grenoble, France

    Hassan Belrhali

Authors
  1. Sameena Khan
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  2. Arvind Sharma
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  3. Hassan Belrhali
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  4. Manickam Yogavel
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  5. Amit Sharma
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Correspondence to Amit Sharma.

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Khan, S., Sharma, A., Belrhali, H. et al. Structural basis of malaria parasite lysyl-tRNA synthetase inhibition by cladosporin. J Struct Funct Genomics 15, 63–71 (2014). https://doi.org/10.1007/s10969-014-9182-1

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  • DOI: https://doi.org/10.1007/s10969-014-9182-1

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