Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Journal of Structural and Functional Genomics

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

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

References

  1. Ibba M, Soll D (2000) Annu. Rev. Biochem. 69:617–650

    Article  CAS  PubMed  Google Scholar 

  2. Jackson KE, Habib S, Frugier M, Hoen R, Khan S et al (2011) Trends Parasitol. 27:467–476

    Article  CAS  PubMed  Google Scholar 

  3. Pham JS, Dawson KL, Jackson KE, Lim EE, Pasaje CF et al (2013) Int. J. Parasitol. Drugs Drug Resist. 4:1–13

    Article  PubMed Central  PubMed  Google Scholar 

  4. Bhatt TK, Kapil C, Khan S, Jairajpuri MA, Sharma V et al (2009) BMC Genom. 10:644

    Article  Google Scholar 

  5. Bhatt TK, Khan S, Dwivedi VP, Banday MM, Sharma A et al (2011) Nat. Commun. 2:530

    Article  PubMed  Google Scholar 

  6. Istvan ES, Dharia NV, Bopp SE, Gluzman I, Winzeler EA et al (2011) Proc. Natl. Acad. Sci. USA 108:1627–1632

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Khan S, Sharma A, Jamwal A, Sharma V, Pole AK et al (2011) Sci. Rep. 1:188

    Article  PubMed Central  PubMed  Google Scholar 

  8. Hoepfner D, McNamara CW, Lim CS, Studer C, Riedl R et al (2012) Cell Host Microbe 11:654–663

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Khan S, Garg A, Camacho N, Van Rooyen J, Pole AK et al (2013) Acta Crystallogr. D Biol. Crystallogr. 69:785–795

    Article  CAS  PubMed  Google Scholar 

  10. Khan S, Garg A, Sharma A, Camacho N, Picchioni D et al (2013) PLoS ONE 8:e66224

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Azcarate IG, Marin-Garcia P, Camacho N, Perez-Benavente S, Puyet A et al (2013) Br. J. Pharmacol. 169:645–658

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Hoen R, Novoa EM, Lopez A, Camacho N, Cubells L et al (2013) ChemBioChem 14:499–509

    Article  CAS  PubMed  Google Scholar 

  13. Filisetti D, Theobald-Dietrich A, Mahmoudi N, Rudinger-Thirion J, Candolfi E et al (2013) J. Biol. Chem. 288:36361–36371

    Article  CAS  PubMed  Google Scholar 

  14. Koh CY, Kim JE, Napoli AJ, Verlinde CL, Fan E et al (2013) Mol. Biochem. Parasitol. 189:26–32

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Mailu BM, Ramasamay G, Mudeppa DG, Li L, Lindner SE, Peterson MJ et al (2013) J. Biol. Chem. 288:32539–32552

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Khan S, Sharma A, Belrhali H, Yogavel M, Sharma A (2014) J. Struct. Funct. Genom. 15:63–71

    Article  CAS  Google Scholar 

  17. Keller TL, Zocco D, Sundrud MS, Hendrick M, Edenius M et al (2012) Nat. Chem. Biol. 8:311–317

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Zhou H, Sun L, Yang XL, Schimmel P (2013) Nature 494:121–124

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Koepfli JB, Mead JF, Brockman JA Jr (1947) J. Am. Chem. Soc. 69:1837

    Article  CAS  PubMed  Google Scholar 

  20. Coatney GR, Cooper WC, Culwell WB, White WC, Imboden CA Jr (1950) J. Natl. Malar. Soc. 9:183–186

    CAS  PubMed  Google Scholar 

  21. Kikuchi H, Yamamoto K, Horoiwa S, Hirai S, Kasahara R (2006) J. Med. Chem. 49:4698–4706

    Article  CAS  PubMed  Google Scholar 

  22. Kobayashi S, Ueno M, Suzuki R, Ishitani H, Kim HS, Wataya Y (1999) J. Org. Chem. 3:6833–6841

    Article  Google Scholar 

  23. Samant BS, Sukhthankar MG (2009) Med. Chem. 5:293–300

    Article  CAS  PubMed  Google Scholar 

  24. Zhu S, Wang J, Chandrashekar G, Smith E, Liu X et al (2010) Eur. J. Med. Chem. 45:3864–3869

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Derbyshire ER, Mazitschek R, Clardy J (2012) ChemMedChem 7:844–849

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Kikuchi H, Horoiwa S, Kasahara R, Hariguchi N, Matsumoto M et al (2014) Eur. J. Med. Chem. 9:10–19

    Article  Google Scholar 

  27. Halevy O, Nagler A, Levi-Schaffer F, Genina O, Pines M (1996) Biochem. Pharmacol. 11:1057–1063

    Article  Google Scholar 

  28. Pines M, Nagler A (1998) Gen. Pharmacol. 30:445–450

    Article  CAS  PubMed  Google Scholar 

  29. Elkin M, Ariel I, Miao HQ, Nagler A, Pines M, de- Groot N, Hochberg A, Vlodavsky I (1999) Cancer Res. 15:4111–4118

    Google Scholar 

  30. McGaha T, Kodera T, Phelps R, Spiera H, Pines M, Bona C (2002) Autoimmunity 35:277–282

    Article  CAS  PubMed  Google Scholar 

  31. Pines M, Snyder D, Yarkoni S, Nagler A (2003) Biol. Blood Marrow Transpl. 9:417–425

    Article  CAS  Google Scholar 

  32. Son J, Lee EH, Park M, Kim JH, Kim J et al (2013) Acta Crystallogr. D Biol. Crystallogr. 69:2136–2145

    Article  CAS  PubMed  Google Scholar 

  33. Larson ET, Kim JE, Napuli AJ, Verlinde CL, Fan E et al (2012) Acta Crystallogr. D Biol. Crystallogr. 68:1194–1200

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Tonkin CJ, van Dooren GG, Spurck TP, Struck NS, Good RT et al (2004) Mol. Biochem. Parasitol. 137:13–21

    Article  CAS  PubMed  Google Scholar 

  35. Otwinowski Z, Minor W (1997) Methods Enzymol. 276:307–326

    Article  CAS  Google Scholar 

  36. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ (2007) J. Appl. Crystallogr. 40:658–674

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P et al (2011) Acta Crystallogr. D Biol. Crystallogr. 67:235–242

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Matthews BW (1976) Annu. Rev. Phys. Chem. 27:493–523

    Article  CAS  Google Scholar 

  39. Afonine PV, Grosse-Kunstleve RW, Echols N, Headd JJ, Moriarty NW et al (2012) Acta Crystallogr. D Biol. Crystallogr. 68:352–367

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Adams PD, Afonine PV, Bunkoczi G, Chen VB, Davis IW et al (2010) Acta Crystallogr. D Biol. Crystallogr. 66:213–221

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Murshudov GN, Skubak P, Lebedev AA, Pannu NS, Steiner RA et al (2011) Acta Crystallogr. D Biol. Crystallogr. 67:355–367

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Emsley P, Lohkamp B, Scott WG, Cowtan K (2010) Acta Crystallogr. D Biol. Crystallogr. 66(486–501):43

    Google Scholar 

  43. Chen VB, Arendall WB, Headd JJ, Keedy DA, Immormino RM et al (2010) Acta Crystallogr. D Biol. Crystallogr. 66:12–21

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM et al (2004) J. Comput. Chem. 25:1605–1612

    Article  CAS  PubMed  Google Scholar 

  45. Krissinel E, Henrick K (2007) J. Mol. Biol. 372:774–797

    Article  CAS  PubMed  Google Scholar 

  46. Ruan B, Söll D (2005) J. Biol. Chem. 280:25887–25891

    Article  CAS  PubMed  Google Scholar 

  47. An S, Musier-Forsyth K (2005) J. Biol. Chem. 280:34465–34472

    Article  CAS  PubMed  Google Scholar 

  48. Doerig C, Baker D, Billker O, Blackman MJ, Chitnis C et al (2009) Parasite 16:169–182

    Article  CAS  PubMed  Google Scholar 

  49. Hora R, Bridges DJ, Craig A, Sharma A (2009) J. Biol. Chem. 284:6260–6269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Sharma A, Yogavel M, Akhouri RR, Gill J, Sharma A (2008) J. Biol. Chem. 283:24077–24088

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Gill J, Yogavel M, Kumar A, Belrhali H, Jain SK et al (2009) J. Biol. Chem. 284:10076–10087

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Gowri VS, Ghosh I, Sharma A, Madhubala R (2012) BMC Genom. 14:621

    Article  Google Scholar 

  53. Van Rooyen JM, Murat JB, Hammoudi PM, Kieffer-Jaquinod S, Coute Y et al (2014) PLoS ONE 20:e89487

    Article  Google Scholar 

  54. Bhatt TK, Yogavel M, Wydau S, Berwal R, Sharma A (2010) J. Biol. Chem. 285:5917–5930

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

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

    Vitul Jain, Amit Sharma & Manickam Yogavel

  2. Laboratory of Natural Product Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-yama, Aoba-ku, Sendai, 980-8578, Japan

    Haruhisa Kikuchi & Yoshiteru Oshima

Authors
  1. Vitul Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haruhisa Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshiteru Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amit Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manickam Yogavel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manickam Yogavel.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jain, V., Kikuchi, H., Oshima, Y. et al. Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase. J Struct Funct Genomics 15, 181–190 (2014). https://doi.org/10.1007/s10969-014-9186-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10969-014-9186-x

Keywords

Search

Navigation