Journal of Structural and Functional Genomics

, Volume 15, Issue 4, pp 181–190 | Cite as

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

  • Vitul Jain
  • Haruhisa Kikuchi
  • Yoshiteru Oshima
  • Amit Sharma
  • Manickam YogavelEmail author


Aminoacyl-tRNA synthetases (aaRSs) drive protein translation in cells and hence these are essential enzymes across life. Inhibition of these enzymes can halt growth of an organism by stalling protein translation. Therefore, small molecule targeting of aaRS active sites is an attractive avenue from the perspective of developing anti-infectives. Febrifugine and its derivatives like halofuginone (HF) are known to inhibit prolyl-tRNA synthetase of malaria parasite Plasmodium falciparum. Here, we present functional and crystallographic data on P. falciparum prolyl-tRNA synthetase (PfPRS). Using immunofluorescence data, we show that PfPRS is exclusively resident in the parasite cytoplasm within asexual blood stage parasites. The inhibitor HF interacts strongly with PfPRS in a non-competitive binding mode in presence or absence of ATP analog. Intriguingly, the two monomers that constitute dimeric PfPRS display significantly different conformations in their active site regions. The structural analyses presented here provide a framework for development of febrifugine derivatives that can seed development of new anti-malarials.


Crystal structure Halofuginone Inhibition Malaria Protein translation 



Aminoacyl-tRNA synthetases


Adenosine 5′-(β,γ-imido) triphosphate


Asymmetric unit


Adenosine triphosphate






Protein data bank


Prolyl-tRNA synthetase


Plasmodium falciparum prolyl-tRNA synthetase





The authors thank X-ray diffraction facility at National Institute of Immunology (NII), New Delhi. VJ is supported by Department of Biotechnology (DBT) Senior Research Fellowship. This research was supported by DBT, Government of India OSRP grant PR6303 to AS, and DBT grant PR3084 to AS and MY.


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Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Vitul Jain
    • 1
  • Haruhisa Kikuchi
    • 2
  • Yoshiteru Oshima
    • 2
  • Amit Sharma
    • 1
  • Manickam Yogavel
    • 1
    Email author
  1. 1.Structural and Computational Biology GroupInternational Centre for Genetic Engineering and Biotechnology (ICGEB)New DelhiIndia
  2. 2.Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan

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