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Biotechnology Letters

, Volume 37, Issue 5, pp 1003–1011 | Cite as

Exploring the impact of F270V mutation in the β-tubulin (Bos Taurus) structure and its function: a computational perspective

  • Kanika Verma
  • K. RamanathanEmail author
Original Research Paper

Abstract

Paclitaxel is the most effective chemotherapeutic agent used for the treatment of a broad spectrum of solid tumors. However, observed paclitaxel resistance in clinical trials presents one of the major obstacles for cancer chemotherapy. Most importantly, resistance due to β-tubulin mutations (F270V) has been intensely debated in recent years. Despite all efforts, mechanism of resistance is still not well understood. In this study, computational techniques were employed to uncover the effect of F270V mutation in the β-tubulin structure and its function. The tools such as MuStab, CUPSAT and I-Mutant were employed to address the consequence of F270V mutation in the structural stability of β-tubulin. Further, molecular simulation study was employed to understand the functional impact of β-tubulin mutation. We believe that this study will provide useful guidance for the development of novel inhibitors that are less susceptible to drug resistance.

Keywords

F270V mutation Molecular docking Molecular dynamics Paclitaxel 

Notes

Acknowledgments

The authors of the manuscript would like to thank the management of VIT University for providing the facility and support to carry out this research work. We sincerely thank reviewers for their valuable comments and suggestions for the improvement of this manuscript. The authors also thank Professor M.A. Mohamed Sahul Hameed, English division, for English editing and grammar corrections.

References

  1. Berrieman HK, Lind MJ, Cawkwell L (2004) Do beta-tubulin mutations have a role in resistance to chemotherapy? Lancet Oncol 5:158–164CrossRefPubMedGoogle Scholar
  2. Choi CH (2005) ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 5:30CrossRefPubMedCentralPubMedGoogle Scholar
  3. Choudhury D, Ganguli A, Dastidar DG, Acharya BR, Das A, Chakrabarti G (2013) Apigenin shows synergistic anticancer activity with curcumin by binding at different sites of tubulin. Biochimie 5(6):1297–1309CrossRefGoogle Scholar
  4. Contini A, Cappelletti G, Cartelli D, Fontana G, Gelmi ML (2012) Molecular dynamics and tubulin polymerization kinetics study on 1,14-heterofused taxanes: evidence of stabilization of the tubulin head-to-tail dimer-dimer interaction. Mol BioSyst 8(12):3254–3261CrossRefPubMedGoogle Scholar
  5. Darden T, Perera L, Li L, Pedersen L (1999) New tricks for modelers from the crystallography toolkit: the particle mesh Ewald algorithm and its use in nucleic acid simulations. Structure 7(3):55–60CrossRefGoogle Scholar
  6. Drukman S, Kavallaris M (2002) Microtubule alterations and resistance to tubulin-binding agents (review). Int J Oncol 21:621–628PubMedGoogle Scholar
  7. Dumontet C, Sikic BI (1999) Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. J Clin Oncol 17:1061–1070PubMedGoogle Scholar
  8. Durrant JD, McCammon JA (2011) Molecular dynamics simulations and drug discovery. BMC Biol 9:71–79CrossRefPubMedCentralPubMedGoogle Scholar
  9. Elengoe A, Naser MA, Hamdan S (2014) Modeling and docking studies on novel mutants (K71L and T204V) of the ATPase domain of human heat shock 70 kDa protein 1. Int J Mol Sci 15(4):6797–6814CrossRefPubMedCentralPubMedGoogle Scholar
  10. Entwistle RA, Winefield RD, Foland TB, Lushington GH, Himes RH (2008) The paclitaxel site in tubulin probed by site-directed mutagenesis of Saccharomyces cerevisiae beta-tubulin. FEBS Lett 582(16):2467–2470CrossRefPubMedCentralPubMedGoogle Scholar
  11. Feldman HJ, Snyder KA, Ticoll A, Pintilie G, Hogue CW (2006) A complete small molecule dataset from the protein data bank. FEBS Lett 580(6):1649–1653CrossRefPubMedGoogle Scholar
  12. Ganesh T, Guza RC, Bane S, Ravindra R, Shanker N, Lakdawala AS, Snyder JP, Kingston DG (2004) The bioactive Taxol conformation on beta-tubulin: experimental evidence from highly active constrained analogs. Proc Natl Acad Sci USA 101(27):10006–10011CrossRefPubMedCentralPubMedGoogle Scholar
  13. Gascoigne KE, Taylor SS (2009) How do anti-mitotic drugs kill cancer cells? J Cell Sci 122:2579–2585CrossRefPubMedGoogle Scholar
  14. Gasteiger J, Rudolph C, Sadowski J (1990) Automatic generation of 3D-atomic coordinates for organic molecules. Tetrahedron Comput Methodol 3:537–547CrossRefGoogle Scholar
  15. Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18(15):2714–2723CrossRefPubMedGoogle Scholar
  16. Hari M, Loganzo F, Annable T, Tan X, Musto S, Morilla DB, Nettles JH, Snyder JP, Greenberger LM (2006) Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (Asp26Glu) and less stable microtubules. Mol Cancer Ther 5(2):270–278CrossRefPubMedGoogle Scholar
  17. He L, Jagtap PG, Kingston DG, Shen HJ, Orr GA, Horwitz SB (2000) A common pharmacophore for Taxol and the epothilones based on the biological activity of a taxane molecule lacking a C-13 side chain. Biochemistry 9(14):3972–3978CrossRefGoogle Scholar
  18. He L, Yang CP, Horwitz SB (2001) Mutations in beta-tubulin map to domains involved in regulation of microtubule stability in epothilone-resistant cell lines. Mol Cancer Ther 1:3–10PubMedGoogle Scholar
  19. Iman M, Davood A, Nematollahi AR, Dehpoor AR, Shafiee A (2011) Design and synthesis of new 1,4-dihydropyridines containing 4(5)-chloro-5(4)-imidazolyl substituent as a novel calcium channel blocker. Arch Pharm Res 34(9):1417–1426CrossRefPubMedGoogle Scholar
  20. Iman M, Saadabadi A, Davood A, Iran J (2013) Docking studies of phthalimide pharmacophore as a sodium channel blocker. Basic Med Sci 16(9):1016–1021Google Scholar
  21. Jordan A, Hadfield JA, Lawrence NJ, McGown AT (1998) Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle. Med Res Rev 18:259–296CrossRefPubMedGoogle Scholar
  22. Khan S, Vihinen M (2010) Performance of protein stability predictors. Hum Mutat 31(6):675–684CrossRefPubMedGoogle Scholar
  23. Lin Y, Yoo S, Sanchez R (2012) SiteComp: a server for ligand binding site analysis in protein structures. Bioinformatics 28(8):1172–1173CrossRefPubMedCentralPubMedGoogle Scholar
  24. Lindahl E, Hess B, Van der Spoel D (2001) GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Model 7:306–317Google Scholar
  25. Meagher KL, Carlson HA (2005) Solvation influences flap collapse in HIV-1 protease. Proteins 58(1):119–125CrossRefPubMedGoogle Scholar
  26. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791CrossRefPubMedCentralPubMedGoogle Scholar
  27. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Mechanisms of Taxol resistance related to microtubules. Oncogene 22(47):7280–7295CrossRefPubMedCentralPubMedGoogle Scholar
  28. Parthiban V, Gromiha MM, Schomburg D (2006) CUPSAT: prediction of protein stability upon point mutations. Nucleic Acids Res 34:239–242CrossRefGoogle Scholar
  29. Raghav D, Sharma V (2013) An in silico evaluation of deleterious nonsynonymous single nucleotide polymorphisms in the ErbB3 oncogene. Biores Open Access 2(3):206–211CrossRefPubMedCentralPubMedGoogle Scholar
  30. Rathinasamy K, Jindal B, Asthana J, Singh P, Balaji P, Panda D (2010) Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine. BMC Cancer 10:213CrossRefPubMedCentralPubMedGoogle Scholar
  31. Schuttelkopf AW, Van Aalten DM (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 60(Pt 8):1355–1363CrossRefPubMedGoogle Scholar
  32. Shing JC, Choi JW, Chapman R, Schroeder MA, Sarkaria JN, Fauq A, Bram RJ (2014) A novel synthetic 1,3-phenyl bis-urea compound targets microtubule polymerization to cause cancer cell death. Cancer Biol Ther 15(7)Google Scholar
  33. Stewart ZA, Westfall MD, Pietenpol JA (2003) Cell-cycle dysregulation and anticancer therapy. Trends Pharmacol Sci 24:139–145CrossRefPubMedGoogle Scholar
  34. Teng S, Srivastava AK, Wang L (2010) Sequence feature-based prediction of protein stability changes upon amino acid substitutions. BMC Genomics 11(2):S5CrossRefPubMedCentralPubMedGoogle Scholar
  35. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26(16):1701–1718CrossRefGoogle Scholar
  36. Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G (2010) Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinform 11:548CrossRefGoogle Scholar
  37. Vydra N, Toma A, Glowala-Kosinska M, Gogler-Piglowska A, Widlak W (2013) Overexpression of heat Shock transcription factor 1 enhances the resistance of melanoma cells to doxorubicin and paclitaxel. BMC Cancer 13:504CrossRefPubMedCentralPubMedGoogle Scholar
  38. Wang HW, Nogales E (2005) Nucleotide-dependent bending flexibility of tubulin regulates microtubule assembly. Nature 435:911–915CrossRefPubMedCentralPubMedGoogle Scholar
  39. Xu S, Chi S, Jin Y, Shi Q, Ge M, Wang S, Zhang X (2012) Molecular dynamics simulation and density functional theory studies on the active pocket for the binding of paclitaxel to tubulin. J Mol Model 18(1):377–391CrossRefPubMedGoogle Scholar
  40. Yin S, Bhattacharya R, Cabral F (2010) Human mutations that confer paclitaxel resistance. Mol Cancer Ther 9(2):327CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Industrial Biotechnology Division, School of Bio Sciences and TechnologyVIT UniversityVelloreIndia

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