Skip to main content
SpringerLink
Log in

Structural effects and competition mechanisms targeting the interactions between p53 and MDM2 for cancer therapy

  • Research article
  • Published:
Frontiers of Physics Aims and scope Submit manuscript

Abstract

Approximately half of all human cancers show normal TP53 gene expression but aberrant overexpression of MDM2 and/or MDMX. This fact suggests a promising cancer therapeutic strategy in targeting the interactions between p53 and MDM2/MDMX. To help realize the goal of developing effective inhibitors to disrupt the p53–MDM2/MDMX interaction, we systematically investigated the structural and interaction characteristics of p53 with inhibitors of its interactions with MDM2 and MDMX from an atomistic perspective using stochastic molecular dynamics simulations. We found that some specific α helices in the structures of MDM2 and MDMX play key roles in their binding to inhibitors, and that the hydrogen bond formed by the Trp23 residue of p53 with its counterpart in MDM2 or MDMX determines the dynamic competition processes of the disruption of the MDM2–p53 interaction and replacement of p53 from the MDM2–p53 complex in vivo. The results reported in this paper are expected to provide basic information for designing functional inhibitors and realizing new strategies of cancer gene therapy.

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

Similar content being viewed by others

References

  1. G. M. Popowicz, A. Dömling, and T. A. Holak, The Structure-Based Design of MDM2/MDMX-p53 Inhibitors Gets Serious, Angew. Chem. Int. Ed. 50(12), 2680 (2011)

    Article  Google Scholar 

  2. X. Wang, J. Wang, and X. Jiang, MDMX protein is essential for MDM2 protein-mediated p53 polyubiquitination, J. Biochem. 286, 23725 (2011)

    Google Scholar 

  3. L. T. Vassilev, B. T. Vu, B. Graves, D. Carvajal, F. Podlaski, Z. Filipovic, N. Kong, U. Kammlott, C. Lukacs, C. Klein, N. Fotouhi, and E. A. Liu, In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, Science 303(5659), 844 (2004)

    Article  ADS  Google Scholar 

  4. P. H. Kussie, S. Gorina, V. Marechal, B. Elenbaas, J. Moreau, A. J. Levine, and N. P. Pavletich, Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain, Science 274(5289), 948 (1996)

    Article  ADS  Google Scholar 

  5. P. Chène, Inhibiting the p53-MDM2 interaction: an important target for cancer therapy, Nat. Rev. Cancer 3(2), 102 (2003)

    Article  Google Scholar 

  6. M. R. Arkin and J. A. Wells, Small-molecule inhibitors of protein-protein interactions progressing towards the dream, Nat. Rev. Drug Discov. 3(4), 301 (2004)

    Article  Google Scholar 

  7. D. C. Fry and L. T. Vassilev, Targeting protein-protein interactions for cancer therapy, J. Mol. Med. (Berl.) 83(12), 955 (2005)

    Article  Google Scholar 

  8. M. Bista, S. Wolf, K. Khoury, K. Kowalska, Y. Huang, E. Wrona, M. Arciniega, G. M. Popowicz, T. A. Holak, and A. Dömling, Transient protein states in designing inhibitors of the p53-MDM2 interaction, Structure 21(12), 2143 (2013)

    Article  Google Scholar 

  9. K. K. Hoe, C. S. Verma, and D. P. Lane, Drugging the p53 pathway: Understanding the route to clinical efficacy, Nat. Rev. Drug Discov. 13(3), 217 (2014)

    Article  Google Scholar 

  10. T. Saha, R. K. Kar, and G. Sa, Structural and sequential context of p53: A review of experimental and theoretical evidence, Prog. Biophys. Mol. Biol. 117(2–3), 250 (2015)

    Article  Google Scholar 

  11. S. Tovar, B. Graves, K. Packman, Z. Filipovic, B. H. M. Xia, C. Tardell, R. Garrido, E. Lee, K. Kolinsky, K. H. To, M. Linn, F. Podlaski, P. Wovkulich, B. Vu, and L. T. Vassilev, MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models, Cancer Res. 73(8), 2587 (2013)

    Article  Google Scholar 

  12. L. Y. Qin, F. Yang, C. Zhou, Y. Chen, H. Zhang, and Z. Su, Efficient reactivation of p53 in cancer cells by a dual MDMX/MDM2 inhibitor, J. Am. Chem. Soc. 136(52), 18023 (2014)

    Article  Google Scholar 

  13. U. M. Moll and O. Petrenko, The MDM2-p53 interaction, Mol. Cancer Res. 1, 1001 (2003)

    Google Scholar 

  14. R. Stad, N. A. Little, D. P. Xirodimas, R. Frenk, A. J. van der Eb, D. P. Lane, M. K. Saville, and A. G. Jochemsen, MDMX stabilizes p53 and MDM2 via two distinct mechanisms, EMBO Rep. 2(11), 1029 (2001)

    Article  Google Scholar 

  15. S. Shangary and S. Wang, Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: A novel approach for cancer therapy, Annu. Rev. Pharmacol. Toxicol. 49(1), 223 (2009)

    Article  Google Scholar 

  16. M. D. M. AbdulHameed, A. Hamza, and C. G. Zhan, Microscopic modes and free energies of 3-phosphoinositide-dependent kinase-1 (PDK1) binding with celecoxib and other inhibitors, J. Phys. Chem. B 110(51), 26365 (2006)

    Article  Google Scholar 

  17. G. Popowicz, A. Czarna, and T. Holak, Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain, Cell Cycle 7(15), 2441 (2008)

    Article  Google Scholar 

  18. B. Anil, C. Riedinger, J. A. Endicott, and M. E. M. Noble, The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant, Acta Crystallogr. D Biol. Crystallogr. 69(8), 1358 (2013)

    Article  Google Scholar 

  19. W. J. Jorgensen, J. Chandrasekhar, J. D. Madura, R. W. Impey, and M. L. Klein, Comparison of simple potential functions for simulating liquid water, J. Chem. Phys. 79(2), 926 (1983)

    Article  ADS  Google Scholar 

  20. W. Humphrey, A. Dalke, and K. Schulten, VMD: Visual molecular dynamics, J. Mol. Graph. 14(1), 33 (1996)

    Article  Google Scholar 

  21. J. C. Phillips, R. Braun, W. Wang, J. Gumbart, E. Tajkhorshid, E. Villa, C. Chipot, R. D. Skeel, L. Kalé, and K. Schulten, Scalable molecular dynamics with NAMD, J. Comput. Chem. 26(16), 1781 (2005)

    Article  Google Scholar 

  22. A. D. Jr MacKerell, D. Bashford, M. Bellott, R. L. Jr Dunbrack, J. D. Evanseck, et al., All-atom empirical potential for molecular modeling and dynamics studies of proteins, J. Phys. Chem. 102(18), 3586 (1998)

    Article  Google Scholar 

  23. S. Shangary, D. Qin, D. McEachern, M. Liu, R. S. Miller, S. Qiu, Z. Nikolovska-Coleska, K. Ding, G. Wang, J. Chen, D. Bernard, J. Zhang, Y. Lu, Q. Gu, R. B. Shah, K. J. Pienta, X. Ling, S. Kang, M. Guo, Y. Sun, D. Yang, and S. Wang, Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition, Proc. Natl. Acad. Sci. USA 105(10), 3933 (2008)

    Article  ADS  Google Scholar 

  24. B. Hu, D. M. Gilkes, B. Farooqi, S. M. Sebti, and J. Chen, MDMX overexpression prevents p53 activation by the MDM2 inhibitor nutlin, J. Biol. Chem. 281(44), 33030 (2006)

    Article  Google Scholar 

  25. N. A. Laurie, S. L. Donovan, C. S. Shih, J. Zhang, N. Mills, C. Fuller, A. Teunisse, S. Lam, Y. Ramos, A. Mohan, D. Johnson, M. Wilson, C. Rodriguez-Galindo, M. Quarto, S. Francoz, S. M. Mendrysa, R. Kiplin Guy, J. C. Marine, A. G. Jochemsen, and M. A. Dyer, Inactivation of the p53 pathway in retinoblastoma, Nature 444(7115), 61 (2006)

    Article  ADS  Google Scholar 

  26. V. Hariharan and W. O. Hancock, Insights into the mechanical properties of the kinesin neck linker domain from sequence analysis and molecular dynamics simulations, Cell. Mol. Bioeng. 2(2), 177 (2009)

    Article  Google Scholar 

  27. J. D. Oliner, K. W. Kinzler, P. S. Meltzer, D. L. George, and B. Vogelstein, Amplification of a gene encoding a p53-associated protein in human sarcomas, Nature 358(6381), 80 (1992)

    Article  ADS  Google Scholar 

  28. J. D. Oliner, J. A. Pietenpol, S. Thiagalingam, J. Gyuris, K. W. Kinzler, and B. Vogelstein, Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53, Nature 362(6423), 857 (1993)

    Article  ADS  Google Scholar 

  29. S. M. Abdur Rauf, H. Takaba, C. A. Del Carpio, and A. Miyamoto, How Nutlin-3 disrupts the MDM2–p53 interaction: A theoretical investigation, Med. Chem. Res. 23(4), 1998 (2014)

    Article  Google Scholar 

  30. M. A. McCoy, J. J. Gesell, M. M. Senior, and D. F. Wyss, Flexible lid to the p53-binding domain of human MDM2: Implications for p53 regulation, Proc. Natl. Acad. Sci. USA 100(4), 1645 (2003)

    Article  ADS  Google Scholar 

  31. S. A. Showalter, L. Bruschweiler-Li, E. Johnson, F. Zhang, and R. Brüschweiler, quantitative lid dynamics of MDM2 reveals differential ligand binding modes of the p53-binding cleft, J. Am. Chem. Soc. 130(20), 6472 (2008)

    Article  Google Scholar 

  32. C. Y. Zhan, K. Varney, W. Y. Yuan, L. Zhao, and W. Lu, Interrogation of MDM2 phosphorylation in p53 activation using native chemical ligation: The functional role of Ser17 phosphorylation in MDM2 reexamined, J. Am. Chem. Soc. 134(15), 6855 (2012)

    Article  Google Scholar 

  33. A. C. Joerger and A. R. Fersht, Structural biology of the tumor suppressor p53, Annu. Rev. Biochem. 77(1), 557 (2008)

    Article  Google Scholar 

  34. K. M. ElSawy, C. S. Verma, T. L. Joseph, D. P. Lane, R. Twarock, and L. Caves, On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: A Brownian dynamics study, Cell Cycle 12(3), 394 (2013)

    Article  Google Scholar 

  35. L. Hernychova, P. Man, C. Verma, J. Nicholson, C.A. Sharma, E. Ruckova, J. Y. Teo, K. Ball, B. Vojtesek, and T. R. Hupp, Identification of a second Nutlin-3 responsive interaction site in the N-terminal domain of MDM2 using hydrogen/deuterium exchange mass spectrometry, Proteomics 13(16), 2512 (2013)

    Article  Google Scholar 

  36. K. Puszynski, A. Gandolfi, and A. d’Onofrio, The pharmacodynamics of the p53-MDM2 targeting drug nutlin: The role of gene-switching noise, PLOS Comput. Biol. 10(12), e1003991 (2014)

    Article  ADS  Google Scholar 

  37. S. X. Liu, Y. Z. Geng, and S. W. Yan, Researches on inhibitors of p53-MDM2 interaction, Prog. Biochem. Biophys. (to be published)

  38. B. Liu, S. W. Yan, and X. F. Gao, Noise amplification in human tumor suppression following gamma irradiation, PLoS One 6(8), e22487 (2011)

    Article  ADS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Nature Science Foundation of China (Grant Nos. 11675018, 10975019, 11605038, and 11545014), Beijing Natural Science Foundation (Grant No. 1172008), and the Fundamental Research Funds for the Central Universities (Grant No. 2015KJJCB01).

Author information

Authors and Affiliations

  1. College of Nuclear Science and Technology, Beijing Normal University, Beijing, 100875, China

    Shu-Xia Liu & Shi-Wei Yan

  2. School of Science, Hebei University of Technology, Tianjin, 300401, China

    Yi-Zhao Geng

  3. Beijing Radiation Center, Beijing, 100875, China

    Shi-Wei Yan

Authors
  1. Shu-Xia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-Zhao Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shi-Wei Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shi-Wei Yan.

Additional information

arXiv: 1701.04967.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, SX., Geng, YZ. & Yan, SW. Structural effects and competition mechanisms targeting the interactions between p53 and MDM2 for cancer therapy. Front. Phys. 12, 128908 (2017). https://doi.org/10.1007/s11467-017-0667-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11467-017-0667-9

Keywords

Search

Navigation