Skip to main content

Advertisement

SpringerLink
Log in

Rational design of the survivin/CDK4 complex by combining protein–protein docking and molecular dynamics simulations

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

Abstract

Survivin, the smallest inhibitor of apoptosis protein (IAP), is a valid target for cancer research. It mediates both the apoptosis pathway and the cell cycle and has been proposed to form a complex with the cyclin-dependent kinase protein CDK4. The resulting complex transports CDK4 from the cytosol to the nucleus, where CDK4 participates in cell division. Survivin has been recognized as a node protein that interacts with several partners; disruption of the formed complexes can lead to new anticancer compounds. We propose a rational model of the survivin/CDK4 complex that fulfills the experimental evidence and that can be used for structure-based design of inhibitors modifying its interface recognition. In particular, the suggested complex involves the alpha helical domain of survivin and resembles the mode of binding of survivin in the survivin/borealin X-ray structure. The proposed model has been obtained by combining protein–protein docking, fractal-based shape complementarity, electrostatics studies and extensive molecular dynamics simulations.

Proposed model of the survivin/CDK4 complex with a close view of the best model refined through molecular dynamics simulations

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, Rago C, Lal A, Wang CJ, Beaudry GA, Ciriello KM, Cook BP, Dufault MR, Ferguson AT, Gao Y, He TC, Hermeking H, Hiraldo SK, Hwang PM, Lopez MA, Luderer HF, Mathews B, Petroziello JM, Polyak K, Zawel L, Zhang W, Zhang X, Zhou W, Haluska FG, Jen J, Sukumar S, Landes GM, Riggins GJ, Vogelstein B, Kinzler KW (1999) Analysis of human transcriptomes. Nat Genet 23:387–388

    Article  CAS  Google Scholar 

  2. Altieri DC (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8:61–70

    Article  CAS  Google Scholar 

  3. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826

    Article  CAS  Google Scholar 

  4. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5:876–885

    Article  CAS  Google Scholar 

  5. Sun C, Nettesheim D, Liu Z, Olejniczak ET (2005) Solution structure of human Survivin and its binding interface with Smac/Diablo. Biochemistry 44:11–17

    Article  CAS  Google Scholar 

  6. Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K, Marusawa H, Zou H, Armstrong R, Matsuzawa S, Salvesen GS, Reed JC, Altieri DC (2004) An IAP–IAP complex inhibits apoptosis. J Biol Chem 279:34087–34090

    Article  CAS  Google Scholar 

  7. Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC, Sessa WC, Altieri DC (2003) Regulation of survivin function by Hsp90. Proc Natl Acad Sci USA 100:13791–13796

    Article  CAS  Google Scholar 

  8. Wheatley SP, Henzing AJ, Dodson H, Khaled W, Earnshaw WC (2004) Aurora-B phosphorylation in vitro identifies a residue of survivin that is essential for its localization and binding to inner centromere protein (INCENP) in vivo. J Biol Chem 279:5655–5660

    Article  CAS  Google Scholar 

  9. Bourhis E, Hymowitz SG, Cochran AG (2007) The mitotic regulator Survivin binds as a monomer to its functional interactor Borealin. J Biol Chem 282:35018–35023

    Article  CAS  Google Scholar 

  10. Suzuki A, Hayashida M, Ito T, Kawano H, Nakano T, Miura M, Akahane K, Shiraki K (2000) Survivin initiates cell cycle entry by the competitive interaction with Cdk4/p16INK4a and Cdk2/Cyclin E complex activation. Oncogene 19:3225–3234

    Article  CAS  Google Scholar 

  11. Suzuki A, Ito T, Kawano H, Hayashida M, Hayasaki Y, Tsutomi Y, Akahane K, Nakano T, Miura M, Shiraki K (2000) Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death. Oncogene 19:1346–1353

    Article  CAS  Google Scholar 

  12. Ai MD, Li LL, Zhao XR, Wu Y, Gong JP, Cao Y (2005) Regulation of Survivin and CDK4 by Epstein-Barr virus encoded latent membrane protein 1 in nasopharyngeal carcinoma cell lines. Cell Res 15:777–784

    Article  CAS  Google Scholar 

  13. Zhang L, Liu J, Lin H, Hu Q, Liu A, Hu Y (2006) Expression of survivin, CDK4, Ki-67 and clinical significance in pediatric acute leukemia. J Huazhong Univ Sci Technol 26:552–554

    Article  Google Scholar 

  14. Chantalat L, Skoufias DA, Kleman JP, Jung B, Dideberg O, Margolis RL (2000) Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. Mol Cell 6:183–189

    CAS  Google Scholar 

  15. Day PJ, Cleasby A, Tickle IJ, O'Reilly M, Coyle JE, Holding FP, McMenamin RL, Yon J, Chopra R, Lengauer C, Jhoti H (2009) Crystal structure of human CDK4 in complex with a D-type cyclin. Proc Natl Acad Sci USA 106:4166–4170

    Article  CAS  Google Scholar 

  16. Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP (1998) Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature 395:237–243

    Article  CAS  Google Scholar 

  17. ALIGN, http://xylian.igh.cnrs.fr/bin/align-guess.cgi

  18. Humphrey W, Dalke A, Schulten K (1996) VMD-visual molecular dynamics. J Mol Graph 14:33–38

    Article  CAS  Google Scholar 

  19. Eswar N, Mari-Renom MA, Webb B, Madhusudhan MS, Eramian D, Shen M, Pieper U, Sali A (2006) Comparative protein structure modeling with MODELLER. Current protocols in Bioinformatics. Supplement 15, Wiley, New York, pp 5.6.1–5.6.30, 200

  20. MOE: Molecular Operating Environment; Chemical Computing Group, Inc. http://www.chemcomp.com/

  21. Wang J, Cieplak P, Kollman PA (2000) How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? J Comput Chem 21:1049–1074

    Article  CAS  Google Scholar 

  22. Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ (2005) PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 33:W363–W367

    Article  CAS  Google Scholar 

  23. Gray JJ, Moughan SE, Wang C, Schueler-Furman O, Kuhlman B, Rohl CA, Baker D (2003) Protein–protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations. J Mol Biol 331:281–299

    Article  CAS  Google Scholar 

  24. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci USA 98:10037–10041

    Article  CAS  Google Scholar 

  25. PyMOL Molecular Graphics System, Version 1.3, Schrödinger, LLC. http://www.pymol.org

  26. Renthal R (1999) Transmembrane and water-soluble helix bundles display reverse patterns of surface roughness. Biochem Biophys Res Commun 263:714–717

    Article  CAS  Google Scholar 

  27. Sanner MF, Olson AJ, Spehner JC (1996) Reduced surface: an efficient way to compute molecular surfaces. Biopolymers 38:305–320

    Article  CAS  Google Scholar 

  28. Pang YP, Xu K, El Yazla J, Prendergast F (2000) Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach. Protein Sci 9:1857–1865

    CAS  Google Scholar 

  29. Obiol-Pardo C, Rubio-Martínez J (2007) Comparative evaluation of MMPBSA and XSCORE to compute binding free energy in XIAP-peptide complexes. J Chem Inf Model 47:134–142

    Article  CAS  Google Scholar 

  30. Obiol-Pardo C, Granadino-Roldán JM, Rubio-Martínez J (2008) Protein–protein recognition as a first step towards the inhibition of XIAP and Survivin anti-apoptotic proteins. J Mol Recognit 21:190–204

    Article  CAS  Google Scholar 

  31. Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Crowley M, Walker RC, Zhang W, Merz KM, Wang B, Hayik S, Roitberg A, Seabra G, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Mathews DH, Seetin MG, Sagui C, Babin V, Kollman PA (2008) AMBER 10. University of California, San Francisco

    Google Scholar 

  32. Harvey MJ, Giupponi G, de Fabritiis G (2009) ACEMD: accelerating biomolecular dynamics in the microsecond time scale. J Chem Theory Comput 5:1632–1639

    Article  CAS  Google Scholar 

  33. Reynolds C, Damerell D, Jones S (2008) ProtorP: a protein—protein interaction analysis server. Bioinformatics 25:413–414

    Article  Google Scholar 

  34. Nooren IM, Thornton JM (2003) Structural characterisation and functional significance of transient protein-protein interactions. J Mol Biol 325:991–1018

    Article  CAS  Google Scholar 

  35. Kaczor AA, Guixà-González R, Carrió P, Obiol-Pardo C, Pastor M, Selent J (2012) Fractal dimension as a measure of surface roughness of G protein-coupled receptors: implications for structure and function. J Mol Model 18:4465–4467

    Google Scholar 

  36. Ross NT, Katt WP, Hamilton AD (2010) Synthetic mimetics of protein secondary structure domains. Phil Trans R Soc A 368:989–1008

    Article  CAS  Google Scholar 

  37. Pavlyukov MS, Antipova NV, Balashova MV, Vinogradova TV, Kopantzev EP, Shakhparanov MI (2011) Survivin monomer plays an essential role in apoptosis regulation. J Biol Chem 286:23296–23307

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This paper was funded by Foundation for Polish Science (FNP, Outgoing Fellowship Kolumb for Agnieszka A. Kaczor).

Author information

Author notes

  1. Cristian Obiol-Pardo

    Present address: Intelligent Pharma, Barcelona Science Park C/ Baldiri Reixac, 4, 08028, Barcelona, Spain

Authors and Affiliations

  1. Research Programme on Biomedical Informatics (GRIB), IMIM/Universitat Pompeu Fabra, Dr. Aiguader 88, 08003, Barcelona, Spain

    Jana Selent, Agnieszka A. Kaczor, Ramon Guixà-González, Pau Carrió, Manuel Pastor & Cristian Obiol-Pardo

  2. Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy, Medical University of Lublin, 4A Chodźki, 20093, Lublin, Poland

    Agnieszka A. Kaczor

Authors
  1. Jana Selent
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Agnieszka A. Kaczor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ramon Guixà-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pau Carrió
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manuel Pastor
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cristian Obiol-Pardo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cristian Obiol-Pardo.

Additional information

Jana Selent and Agnieszka A. Kaczor contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 73 kb)

ESM 2

(PDB 510 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Selent, J., Kaczor, A.A., Guixà-González, R. et al. Rational design of the survivin/CDK4 complex by combining protein–protein docking and molecular dynamics simulations. J Mol Model 19, 1507–1514 (2013). https://doi.org/10.1007/s00894-012-1705-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-012-1705-8

Keywords

Search

Navigation