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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
Article

Abstract

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.

Keywords

Crystal structure Halofuginone Inhibition Malaria Protein translation 

Abbreviations

aaRSs

Aminoacyl-tRNA synthetases

AMPPNP

Adenosine 5′-(β,γ-imido) triphosphate

ASU

Asymmetric unit

ATP

Adenosine triphosphate

HF

Halofuginone

l-Pro

l-proline

PDB

Protein data bank

PRS

Prolyl-tRNA synthetase

PfPRS

Plasmodium falciparum prolyl-tRNA synthetase

RMSD

Root-mean-square-deviation

Notes

Acknowledgments

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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