|
|
|
Structural effects and competition mechanisms targeting the interactions between p53 and MDM2 for cancer therapy |
Shu-Xia Liu1,Yi-Zhao Geng2,Shi-Wei Yan1,3( ) |
1. College of Nuclear Science and Technology, Beijing Normal University, Beijing 100875, China
2. School of Science, Hebei University of Technology, Tianjin 300401, China
3. Beijing Radiation Center, Beijing 100875, China |
|
|
|
|
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.
|
| Keywords
p53
MDMX
MDM2
molecular dynamics simulation
inhibitors
cancer therapy
|
|
Corresponding Author(s):
Shi-Wei Yan
|
|
Issue Date: 13 April 2017
|
|
| 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)
https://doi.org/10.1002/anie.201003863
|
| 2 |
X. Wang, J. Wang, and X. Jiang, MDMX protein is essential for MDM2 protein-mediated p53 polyubiquitination, J. Biochem. 286, 23725 (2011)
https://doi.org/10.1074/jbc.m110.213868
|
| 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)
https://doi.org/10.1126/science.1092472
|
| 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)
https://doi.org/10.1126/science.274.5289.948
|
| 5 |
P. Chène, Inhibiting the p53-MDM2 interaction: an important target for cancer therapy, Nat. Rev. Cancer 3(2), 102 (2003)
https://doi.org/10.1038/nrc991
|
| 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)
https://doi.org/10.1038/nrd1343
|
| 7 |
D. C. Fry and L. T. Vassilev, Targeting protein-protein interactions for cancer therapy, J. Mol. Med. (Berl.) 83(12), 955 (2005)
https://doi.org/10.1007/s00109-005-0705-x
|
| 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)
https://doi.org/10.1016/j.str.2013.09.006
|
| 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)
https://doi.org/10.1038/nrd4236
|
| 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)
https://doi.org/10.1016/j.pbiomolbio.2014.12.002
|
| 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)
https://doi.org/10.1158/0008-5472.CAN-12-2807
|
| 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)
https://doi.org/10.1021/ja509223m
|
| 13 |
U. M. Moll and O. Petrenko, The MDM2-p53 interaction, Mol. Cancer Res. 1, 1001 (2003)
|
| 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)
https://doi.org/10.1093/embo-reports/kve227
|
| 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)
https://doi.org/10.1146/annurev.pharmtox.48.113006.094723
|
| 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)
https://doi.org/10.1021/jp065207e
|
| 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)
https://doi.org/10.4161/cc.6365
|
| 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)
https://doi.org/10.1107/S0907444913004459
|
| 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)
https://doi.org/10.1063/1.445869
|
| 20 |
W. Humphrey, A. Dalke, and K. Schulten, VMD: Visual molecular dynamics, J. Mol. Graph. 14(1), 33 (1996)
https://doi.org/10.1016/0263-7855(96)00018-5
|
| 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)
https://doi.org/10.1002/jcc.20289
|
| 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)
https://doi.org/10.1021/jp973084f
|
| 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)
https://doi.org/10.1073/pnas.0708917105
|
| 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)
https://doi.org/10.1074/jbc.C600147200
|
| 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)
https://doi.org/10.1038/nature05194
|
| 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)
https://doi.org/10.1007/s12195-009-0059-5
|
| 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)
https://doi.org/10.1038/358080a0
|
| 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)
https://doi.org/10.1038/362857a0
|
| 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)
https://doi.org/10.1007/s00044-013-0792-0
|
| 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)
https://doi.org/10.1073/pnas.0334477100
|
| 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)
https://doi.org/10.1021/ja800201j
|
| 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)
https://doi.org/10.1021/ja301255n
|
| 33 |
A. C. Joerger and A. R. Fersht, Structural biology of the tumor suppressor p53, Annu. Rev. Biochem. 77(1), 557 (2008)
https://doi.org/10.1146/annurev.biochem.77.060806.091238
|
| 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)
https://doi.org/10.4161/cc.23511
|
| 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)
https://doi.org/10.1002/pmic.201300029
|
| 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)
https://doi.org/10.1371/journal.pcbi.1003991
|
| 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)
https://doi.org/10.1371/journal.pone.0022487
|
|
Viewed |
|
|
|
Full text
|
|
|
|
|
Abstract
|
|
|
|
|
Cited |
|
|
|
|
| |
Shared |
|
|
|
|
| |
Discussed |
|
|
|
|
