Skip to main content
SpringerLink
Log in

Molecular and structural insight into plasmodium falciparum RIO2 kinase

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Among approximately 65 kinases of the malarial genome, RIO2 (right open reading frame) kinase belonging to the atypical class of kinase is unique because along with a kinase domain, it has a highly conserved N-terminal winged helix (wHTH) domain. The wHTH domain resembles the wing like domain found in DNA binding proteins and is situated near to the kinase domain. Ligand binding to this domain may reposition the kinase domain leading to inhibition of enzyme function and could be utilized as a novel allosteric site to design inhibitor. In the present study, we have generated a model of RIO2 kinase from Plasmodium falciparum utilizing multiple modeling, simulation approach. A novel putative DNA-binding site is identified for the first time in PfRIO2 kinase to understand the DNA binding events involving wHTH domain and flexible loop. Induced fit DNA docking followed by minimization, molecular dynamics simulation, energetic scoring and binding mode studies are used to reveal the structural basis of PfRIO2-ATP-DNA complex. Ser105 as a potential site of phosphorylation is revealed through the structural studies of ATP binding in PfRIO2. Overall the present study discloses the structural facets of unknown PfRIO2 complex and opens an avenue toward exploration of novel drug target.

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
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

DNA:

Deoxyribonucleic acid

ATP:

Adenosine triphosphate

RIO:

Right open reading frame

References

  1. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM (2008) Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 359:2619–2620

    Article  CAS  Google Scholar 

  2. Noedl H, Socheat D, Satimai W (2009) Artemisinin-resistant malaria in Asia. N Engl J Med 361:540–541

    Article  CAS  Google Scholar 

  3. Kumar S, Bandyopadhyay U (2005) Free heme toxicity and its detoxification systems in human. Toxicol Lett 157:175–188

    Article  CAS  Google Scholar 

  4. Becker K, Tilley L, Vennerstrom JL, Roberts D, Rogerson S, Ginsburg H (2004) Oxidative stress in malaria parasite-infected erythrocytes: host–parasite interactions. Int J Parasitol 34:163–189

    Article  CAS  Google Scholar 

  5. Gromer S, Urig S, Becker K (2004) The thioredoxin system—from science to clinic. Med Res Rev 24:40–89

    Article  CAS  Google Scholar 

  6. Müller S (2004) Redox and antioxidant systems of the malaria parasite Plasmodium falciparum. Mol Microbiol 53:1291–1305

    Article  Google Scholar 

  7. Ramya T, Surolia N, Surolia A (2002) Survival strategies of the malarial parasite Plasmodium falciparum. Curr Sci 83:818–825

    CAS  Google Scholar 

  8. Nogueira F, Diez A, Radfar A, Pérez-Benavente S, Rosario VE, Puyet A, Bautista JM (2010) Early transcriptional response to chloroquine of the Plasmodium falciparum antioxidant defence in sensitive and resistant clones. Acta Trop 114:109–115

    Article  CAS  Google Scholar 

  9. Vega-Rodríguez J, Franke-Fayard B, Dinglasan RR, Janse CJ, Pastrana-Mena R, Waters AP, Coppens I, Rodríguez-Orengo JF, Jacobs-Lorena M, Serrano AE (2009) The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission. PLoS Pathog 5:e1000302

    Article  Google Scholar 

  10. Ginsburg H, Stein W (2004) The new permeability pathways induced by the malaria parasite in the membrane of the infected erythrocyte: comparison of results using different experimental techniques. J Membr Biol 197:113–134

    Article  CAS  Google Scholar 

  11. Bruchhaus I, Roeder T, Rennenberg A, Heussler VT (2007) Protozoan parasites: programmed cell death as a mechanism of parasitism. Trends Parasitol 23:376–383

    Article  CAS  Google Scholar 

  12. Vaidya AB, Mather MW (2009) Mitochondrial evolution and functions in malaria parasites. Annu Rev Microbiol 63:249–267

    Article  CAS  Google Scholar 

  13. Dhangadamajhi G, Kar SK, Ranjit M (2010) The survival strategies of malaria parasite in the red blood cell and host cell polymorphisms. Malar Res Treat 2010:973094–973103

    Google Scholar 

  14. Doerig C, Billker O, Haystead T, Sharma P, Tobin AB, Waters NC (2008) Protein kinases of malaria parasites: an update. Trends Parasitol 24:570–577

    Article  CAS  Google Scholar 

  15. Bozdech Z, Zhu J, Joachimiak MP, Cohen FE, Pulliam B, DeRisi JL (2003) Expression profiling of the schizont and trophozoite stages of Plasmodium falciparum with a long-oligonucleotide microarray. Genome Biol 4:R9

    Article  Google Scholar 

  16. Ward P, Equinet L, Packer J, Doerig C (2004) Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote. BMC Genomics 5:79

    Article  Google Scholar 

  17. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934

    Article  CAS  Google Scholar 

  18. Angermayr M, Bandlow W (2002) RIO1, an extraordinary novel protein kinase. FEBS Lett 524:31–36

    Article  CAS  Google Scholar 

  19. Gajiwala KS, Burley SK (2000) Winged helix proteins. Curr Opin Struct Biol 10:110–116

    Article  CAS  Google Scholar 

  20. Wolberger C, Campbell R (2000) New perch for the winged helix. Nat Struct Mol Biol 7:261–262

    Article  CAS  Google Scholar 

  21. Dong G, Chakshusmathi G, Wolin SL, Reinisch KM (2004) Structure of the La motif: a winged helix domain mediates RNA binding via a conserved aromatic patch. EMBO J 23:1000–1007

    Article  CAS  Google Scholar 

  22. Geerlings TH, Faber AW, Bister MD, Vos JC, Raue HA (2003) Rio2p, an evolutionarily conserved, low abundant protein kinase essential for processing of 20S Pre-rRNA in Saccharomyces cerevisiae. J Biol Chem 278:22537–22545

    Article  CAS  Google Scholar 

  23. LaRonde-LeBlanc N, Wlodawer A (2005) The RIO kinases: an atypical protein kinase family required for ribosome biogenesis and cell cycle progression. Biochim Biophys Acta 1754:14–24

    Article  CAS  Google Scholar 

  24. Campbell BE, Boag PR, Hofmann A, Cantacessi C, Wang CK, Taylor P, Hu M, Sindhu ZU, Loukas A, Sternberg PW, Gasser RB (2011) Atypical (RIO) protein kinases from Haemonchus contortus—promise as new targets for nematocidal drugs. Biotechnol Adv 29:338–350

    Article  CAS  Google Scholar 

  25. Campbell BE, Hofmann A, McCluskey A, Gasser RB (2011) Serine/threonine phosphatases in socioeconomically important parasitic nematodes—prospects as novel drug targets? Biotechnol Adv 29:28–39

    Article  CAS  Google Scholar 

  26. Canduri F, Perez PC, Caceres RA, de Azevedo WF Jr (2007) Protein kinases as targets for antiparasitic chemotherapy drugs. Curr Drug Targets 8:389–398

    Article  CAS  Google Scholar 

  27. LaRonde-LeBlanc N, Wlodawer A (2004) Crystal structure of A. fulgidus Rio2 defines a new family of serine protein kinases. Structure 12:1585–1594

    Article  CAS  Google Scholar 

  28. Schrödinger LLC (2011) Schrödinger LLC, New York, NY

  29. Prime. V 3.0 (2011) Schrödinger, LLC, New York, NY, V 3.0, Schrödinger, LLC, New York, NY

  30. Desmond-V-3.0 (2010) Molecular Dynamics System, V 3.0, D. E. Shaw Research, Schrödinger, LLC, New York, NY

  31. Sherman W, Day T, Jacobson MP, Friesner RA, Farid R (2006) Novel procedure for modeling ligand/receptor induced fit effects. J Med Chem 49:534–553

    Article  CAS  Google Scholar 

  32. MacroModel-V-9.9 (2011) Schrödinger LLC, New York, NY

  33. Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S (2002) Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498–511

    Article  CAS  Google Scholar 

  34. Glide-V-5.7. (2011) V 2.5, Schrödinger, LLC, New York, NY

  35. Hoover WG (1985) Canonical dynamics: equilibrium phase-space distributions. Phys Rev A 31:1695–1697

    Article  Google Scholar 

  36. Tobias D, Martyna G, Klein M (1994) Constant pressure molecular dynamics algorithms. J Chem Phys 101:4177

    Article  Google Scholar 

  37. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593

    Article  CAS  Google Scholar 

  38. SiteMap-V-2.5 (2011) V 2.5, Schrödinger, LLC, New York, NY

  39. Halgren TA (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49:377–389

    Article  CAS  Google Scholar 

  40. Nayal M, Honig B (2006) On the nature of cavities on protein surfaces: application to the identification of drug-binding sites. Proteins 63:892–906

    Article  CAS  Google Scholar 

  41. Si J, Zhang Z, Lin B, Schroeder M, Huang B (2011) MetaDBSite: a meta approach to improve protein DNA-binding sites prediction. BMC Syst Biol 5(Suppl 1):S7

    Article  CAS  Google Scholar 

  42. Sherman W, Beard HS, Farid R (2006) Use of an induced fit receptor structure in virtual screening. Chem Biol Drug Des 67:83–84

    Article  CAS  Google Scholar 

  43. Kim YA, Sharon A, Chu CK, Rais RH, Al Safarjalani ON, Naguib FNM, el Kouni MH (2007) Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents. Biochem Pharmacol 73:1558–1572

    Article  CAS  Google Scholar 

  44. Lyne PD, Lamb ML, Saeh JC (2006) Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J Med Chem 49:4805–4808

    Article  CAS  Google Scholar 

  45. DeLano W (2002) The PyMOL molecular graphics system. DeLano Scientific, Palo Alto

    Google Scholar 

  46. Clark KL, Halay ED, Lai E, Burley SK (1993) Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5

  47. Gajiwala KS, Chen H, Cornille F, Roques BP, Reith W, Mach B, Burley SK (2000) Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding. Nature 403:916–921

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research received funding from Department of Biotechnology (DBT), New Delhi, India through grant no BT/41/NE/TBP/2010. Authors' thanks to DBT (BT/PR14237/MED/29/196/2010) for providing Schrödinger Software. DKC is thankful to DBT for the Junior Research Fellowship. Authors are thankful to Dr. Robert J. Woods, Complex Carbohydrate Research Centre, University of Georgia, Athens, USA for critical reading and technical comments, who is also an external Ph. D. supervisor of DKC. We thank Dr. Vishal Trivedi, IIT Guwahati, for helpful discussions on biochemical function of RIO2 Kinase.

Author information

Authors and Affiliations

  1. Department of Applied Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India

    Devendra K. Chouhan, Ashoke Sharon & Chandralata Bal

Authors
  1. Devendra K. Chouhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashoke Sharon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chandralata Bal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chandralata Bal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chouhan, D.K., Sharon, A. & Bal, C. Molecular and structural insight into plasmodium falciparum RIO2 kinase. J Mol Model 19, 485–496 (2013). https://doi.org/10.1007/s00894-012-1572-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-012-1572-3

Keywords

Search

Navigation