Structural effects and competition mechanisms targeting the interactions between p53 and MDM2 for cancer therapy
- 129 Downloads
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.
Keywordsp53 MDMX MDM2 molecular dynamics simulation inhibitors cancer therapy
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).
- 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
- 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)CrossRefGoogle Scholar
- 13.U. M. Moll and O. Petrenko, The MDM2-p53 interaction, Mol. Cancer Res. 1, 1001 (2003)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)ADSCrossRefGoogle 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)ADSCrossRefGoogle 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)CrossRefGoogle 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)Google Scholar