Structural basis of malaria parasite lysyl-tRNA synthetase inhibition by cladosporin
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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.
KeywordsCladosporin KRS Malaria X-ray crystal structure Inhibition
Cambridge crystallographic data centre
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.