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Structure-based Design of High Affinity Peptides Inhibiting the Interaction of p53 with MDM2 and MDMX
Open accessAbstract
MDM2 and MDMX function as key regulators of p53 by binding to its N terminus, inhibiting its transcriptional activity, and promoting degradation. MDM2 and MDMX overexpression or hyperactivation directly contributes to the loss of p53 function during the development of nearly 50% of human cancers. Recent studies showed that disrupting p53-MDM2 and p53-MDMX interactions can lead to robust activation of p53 but also revealed a need to develop novel dual specific or MDMX-specific inhibitors. Using phage display we identified a 12-residue peptide (pDI) with inhibitory activity against MDM2 and MDMX. The co-crystal structures of the pDI and a single mutant derivative (pDI6W) liganded with the N-terminal domains of human MDMX and MDM2 served as the basis for the design of 11 distinct pDI-derivative peptides that were tested for inhibitory potential. The best derivative (termed pDIQ) contained four amino acid substitutions and exhibited a 5-fold increase in potency over the parent peptide against both MDM2 (IC(50) = 8 nm) and MDMX (IC(50) = 110 nm). Further structural studies revealed key molecular features enabling the high affinity binding of the pDIQ to these proteins. These include large conformational changes of the pDIQ to reach into a hydrophobic site unique to MDMX. The findings suggest new strategies toward the rational design of small molecule inhibitors efficiently targeting MDMX.
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Citations
Cites
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,317
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,723
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,616
p53, the cellular gatekeeper for growth and division
Levine, A. J. (1997) · Cell · doi:10.1016/s0092-8674(00)81871-1 · Cited by 7,693
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
A solution for the best rotation to relate two sets of vectors
Kabsch, W. (1976) · Acta Crystallographica Section A · doi:10.1107/s0567739476001873 · Cited by 3,462
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206
Amplification of a gene encoding a p53-associated protein in human sarcomas
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B. (1992) · Nature · doi:10.1038/358080a0 · Cited by 1,949
The p53-mdm-2 autoregulatory feedback loop.
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1126 · Cited by 1,801
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,474
Flagged first, then by citations
Research works printed but not linked: 1
- Chen, 1993, Mol. Cell. Biol., 13, 4107
Cited by
Sorted by citations
Items 101–179 of 179
Grison, C. M., Miles, J. A., Robin, S., Wilson, A. J., & Aitken, D. J. (2016) · Angewandte Chemie · doi:10.1002/ange.201604517 · Cited by 14
Ranking Peptide Binders by Affinity with AlphaFold**
Chang, L., & Pérez, A. (2022) · Angewandte Chemie · doi:10.1002/ange.202213362 · Cited by 16
MDM4 binds ligands via a mechanism in which disordered regions become structured
Sanchez, M. C., Renshaw, J., Davies, G. M., Barlow, P. N., & Vogtherr, M. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.05.058 · Cited by 14
Yang, W., Wang, J., Zhao, L., & Chen, J. (2024) · Molecules · doi:10.3390/molecules29143377 · Cited by 15
Self-citationXu, L., Fan, X., He, Y., Xia, X., & Zhang, J. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01939 · Cited by 14
Therapeutic peptides and their delivery using lipid-based nanoparticles
Yen, J.-H., Chang, C., Wu, T., Yang, C.-H., Hsu, H., & Liou, J.-W. (2025) · Tzu Chi Medical Journal · doi:10.4103/tcmj.tcmj_321_24 · Cited by 13
Zhai, S., Zhao, H., Wang, J., Lin, S., Liu, T., Gu, S., Jiang, D., Liu, H., Kang, Y., Yao, X., et al. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c01084 · Cited by 21
Sedzro, D. M., Idris, M. O., Durojaye, O. A., Yekeen, A. A., Fadahunsi, A. A., & Alakanse, O. S. (2022) · ChemistrySelect · doi:10.1002/slct.202202380 · Cited by 12
The MDMX Acidic Domain Uses Allovalency to Bind Both p53 and MDMX
Fenton, M. J., Borcherds, W. M., Chen, L., Anbanandam, A., Levy, R., Chen, J., & Daughdrill, G. W. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167844 · Cited by 12
Self-citationDezi, C., Carotti, A., Magnani, M., Baroni, M., Padova, A., Cruciani, G., Macchiarulo, A., & Pellicciari, R. (2010) · Journal of Chemical Information and Modeling · doi:10.1021/ci100113p · Cited by 12
Pep–Whisperer: Inhibitory peptide design
Hurwitz, N., Zaidman, D., & Wolfson, H. J. (2022) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26384 · Cited by 12
Chen, T., Sun, T., Bian, Y., Pei, Y., Feng, F., Chi, H., Li, Y., Tang, X., Sang, S., Du, C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01456 · Cited by 11
Rajabi, P., Karimian, P., & Heidarpour, M. (2012) · Europe PMC (PubMed Central) · Cited by 11
Shi, S., Zhang, S., & Zhang, Q. (2015) · PLoS ONE · doi:10.1371/journal.pone.0141409 · Cited by 10
Design of peptides with noncanonical amino acids using flow matching
Lee, J. S., & Kim, P. M. (2026) · Bioinformatics · doi:10.1093/bioinformatics/btag654 · Cited by 12
Identification of a Structural Determinant for Selective Targeting of HDMX
Ben‐Nun, Y., Seo, H., Harvey, E. P., Hauseman, Z. J., Wales, T. E., Newman, C. E., Cathcart, A. M., Engen, J. R., Dhe‐Paganon, S., & Walensky, L. D. (2020) · Structure · doi:10.1016/j.str.2020.04.011 · Cited by 10
Hainaut, P. L., Wiman, K. G., & Olivier, M. (2012) · Springer eBooks · doi:10.1007/978-1-4614-3676-8 · Cited by 10
Neuville, M., Bourgeais, M., Li, B., Varajao, L., Hallé, F., Goudreau, S. R., Thinon, E., Pasco, M., Khatib, A., & Guichard, G. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01762 · Cited by 10
Self-citationElaboration of Non-naturally Occurring Helical Tripeptides as p53–MDM2/MDMX Interaction Inhibitors
Su, A., Tabata, Y., Aoki, K., Sada, A., Ohki, R., Nagatoishi, S., Tsumoto, K., Wang, S., Otani, Y., & Ohwada, T. (2021) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.c21-00238 · Cited by 8
Fujimura, A., Ishida, H., Nozaki, T., Terada, S., Azumaya, Y., Ishiguro, T., Kamimura, Y. R., Kujirai, T., Kurumizaka, H., Kono, H., et al. (2023) · ACS Central Science · doi:10.1021/acscentsci.3c00930 · Cited by 8
Shi, S., Zhang, S., & Zhang, Q. (2014) · Computational and Theoretical Chemistry · doi:10.1016/j.comptc.2014.07.002 · Cited by 8
Huang, A., Zhou, L. Y., Zhang, D., Yao, J., & Zhang, Y. (2016) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2016.09.007 · Cited by 8
Proximity-induced amino-yne reaction for selective MDM4 conjugation via propargylated sulfonium
Lian, C., Li, Y., Hou, Z., Zhong, W., Tian, Y., Yin, F., Li, Z., Zhou, D., & Wang, R. Y. (2021) · Chinese Chemical Letters · doi:10.1016/j.cclet.2021.04.015 · Cited by 8
Self-citationDiller, D., Swanson, J., Bayden, A. S., Brown, C. J., Thean, D., Lane, D. P., Partridge, A. W., Sawyer, T. K., & Audie, J. (2019) · Molecules · doi:10.3390/molecules24244586 · Cited by 7
Identification of Small Molecules Affecting p53-MDM2/MDMX Interaction by Fluorescence Polarization
Zhang, Q., & Lu, H. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-236-0_8 · Cited by 7
Jetzt wird es ernst: strukturbasiertes Design von Mdm2/Mdmx‐p53‐Inhibitoren
Popowicz, G. M., Dömling, A. S. S., & Holak, T. A. (2011) · Angewandte Chemie · doi:10.1002/ange.201003863 · Cited by 7
Li, Y., Yu, X., Lou, Y., & Wang, T. (2016) · Australian Journal of Chemistry · doi:10.1071/ch16096 · Cited by 7
Siriki, A., Ragland, G., Vasireddy, J., & Chitneni, S. K. (2025) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2025.130394 · Cited by 7
Chen, J., Wang, J., Pang, L., & Zhu, W. (2018) · Chemical Biology & Drug Design · doi:10.1111/cbdd.13345 · Cited by 7
Self-citationShi, S., Sui, K., Liu, W., Lei, Y., Zhang, S., & Zhang, Q. (2019) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2019.1695671 · Cited by 6
Kasper, S. H., Otten, S., Squadroni, B., Orr‐Terry, C., Kuang, Y., Mussallem, L., Ge, L., Yan, L. Y., Kannan, S., Verma, C. S., et al. (2023) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10542 · Cited by 5
Peptide and protein chemistry approaches to study the tumor suppressor protein p53
Chatterjee, C., & Singh, S. K. (2022) · Organic & Biomolecular Chemistry · doi:10.1039/d2ob00902a · Cited by 4
Zhao, P. T., Cao, H., Chen, Y., & Zhu, T. (2019) · Chemical Physics Letters · doi:10.1016/j.cplett.2019.05.001 · Cited by 4
Samanta, S., & Mukherjee, S. (2017) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-017-0057-y · Cited by 4
Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment
Sardina, F., Polverino, F., Valentini, S., Carsetti, C., Falvo, E., Tisci, G., Soddu, S., Moretti, F., Paiardini, A., & Rinaldo, C. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02333-y · Cited by 3
Yin, Q., Hu, Y., Dong, Z., Lu, J., & Wang, H. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00913 · Cited by 3
Reengineering of a Proteomimetic Pan‐Ras Inhibitor into a Ras Degrader
Ongkingco, J. F., Hong, S. H., Toth, E. D., Nguyễn, T. T., & Arora, P. S. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202507092 · Cited by 4
Interactions of HIV-1 Proteins as Targets for Developing Anti-HIV-1 Peptides
Chandra, K., Maes, M., & Friedler, A. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.15.46 · Cited by 3
Cheng, W.-Y., Liang, Z., Wang, W., Yi, C., Li, H., Zhang, S., & Zhang, Q. (2015) · Molecular Physics · doi:10.1080/00268976.2015.1087598 · Cited by 3
Regularized indirect learning improves phage display ligand discoveryPreprint
Brown, J. S., Tseo, Y., Lee, M. A., Wong, J. Y. K., Yang, S., Cho, Y., Kim, C. R., Loas, A., Derda, R., Gómez‐Bombarelli, R., et al. (2023) · ChemRxiv · doi:10.26434/chemrxiv-2023-jpwvn · Cited by 3
Polyfluorinated reagents for peptide stapling
Lin, W., Ding, X., Han, J., Yu, L., & Chen, F. (2025) · Organic Chemistry Frontiers · doi:10.1039/d5qo00112a · Cited by 2
Qie, B., Li, J., Wan, M., & Zhu, Y. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.126298 · Cited by 2
Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality
Zhang, X., Yue, H.-W., Liu, Y., Wang, J., Duan, H.-T., Liu, Y.-H., Jiang, L., & Hu, H. (2025) · iScience · doi:10.1016/j.isci.2025.112025 · Cited by 3
Diller, K. I., Bayden, A. S., Audie, J., & Diller, D. (2017) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2017.11.016 · Cited by 2
FLASH-AWAY: Intrabody-Directed Targeting of Optogenetic Tools for Protein Degradation
Zhuang, Z., Li, R., Wang, B., Meng, Y., Li, Y., Nan, J., Zhao, X., & Ji, J. (2025) · ACS Synthetic Biology · doi:10.1021/acssynbio.4c00822 · Cited by 1
De novo grafted coiled-coil peptides as p53/ h DM2 inhibitors
Spain, F., Giménez, D., Acevedo‐Jake, A. M., Mylemans, B., Brooks, N. J., Korona, B., Huang, D. T. C., Edwards, T. A., Leney, A. C., Itzhaki, L. S., et al. (2026) · RSC Chemical Biology · doi:10.1039/d6cb00063k · Cited by 1
Tethered ribozyme ligation enables detection of molecular proximity in homogeneous solutions
Katzman, B., Vyazmensky, M., Press, O., Volokita, M., & Engel, S. (2014) · Biotechnology Journal · doi:10.1002/biot.201400551 · Cited by 1
Yang, Y., Dong, Z., Hu, H., Peng, J., Sheng, Y., Yang, T., Yuan, S., Li, Z., Yang, J., Wells, T., et al. (2019) · The Analyst · doi:10.1039/c9an00350a · Cited by 1
Self-citationLang, L., Frontera, A., Pérez, A., & Bauzá, A. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c00024 · Cited by 1
Donsky, E., & Wolfson, H. J. (2011) · Lecture notes in computer science · doi:10.1007/978-3-642-23038-7_7 · Cited by 1
Upstream Targets in the p53 Pathway
McCarthy, A. R., & Laı́n, S. (2012) · Springer eBooks · doi:10.1007/978-1-4614-3676-8_12
Protein–Protein Interactions as Drug Discovery Targets
Dömling, A. S. S. (2010) · Wiley eBooks · doi:10.1002/0471266949.bmc129
Touqan, N. (2014) · UPT. Syiah Kuala University Library (Syiah Kuala University)
Insight into Interaction Mechanism of the Inhibitor pDI6W with MDM2 Based on Molecular Dynamics
Chen, J., Liang, Z.-Q. L. Z.-Q., Zhang, Q., Liu, X.-Y., Wang, W., & Liu, J.-Q. L. J.-Q. (2013) · The Journal of Atomic and Molecular Sciences · doi:10.4208/jmas.063012.072912a
Self-citationMolecular Dynamics Insight into the Interaction Mechanism of Inhibitor PMI with MDMX
程, 伟. (2012) · Hans Journal of Computational Biology · doi:10.12677/hjcb.2012.23003
Wang, X., Magdziarz, P., Enriquez, E., Zhao, W., Quan, C., Darabedian, N., Momand, J. A., & Zhou, F. (2019) · Analytical Biochemistry · doi:10.1016/j.ab.2019.01.012
Atangcho, L. (2020) · Deep Blue (University of Michigan)
A Novel Intramolecular Interaction in P53
He, F. (2020) · Digital Commons - University of South Florida (University of South Florida)
DIRECT AND INVERSE PROBLEMS FOR THE EVERSION OF A SPHERICAL SHELL
Rosca, R. I., & Drapaca, C. S. (2010)
Applications of Constrained Helices
Li, Z., Zhao, H., & Wan, C. (2021) · Wiley eBooks · doi:10.1002/9783527343430.ch4
Self-citationMolecular Gymnastics Required for Mdmx Inhibition of P53 DNA Binding ActivityPreprint
Fenton, M. J., Borcherds, W. M., Chen, L., Anbanandam, A., Chen, J., & Daughdrill, G. W. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4107498
Self-citationElSawy, K. M., Alminderej, F. M., Verma, C. S., & Caves, L. S. D. (2022) · Molecular Systems Design & Engineering · doi:10.1039/d2me00042c
MDM2 gene a mplification in s kin c ancer p atients
Jabbar, R. A., Ghali, K. H., & Karim, M. N. (2022) · Journal of Wasit for Science and Medicine · doi:10.31185/jwsm.310
Ranking protein-peptide binding affinities with protein language modelsPreprint
Chahla, C., & Dunne, M. P. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.14.623613
Reengineering of a Proteomimetic Pan‐Ras Inhibitor into a Ras Degrader
Ongkingco, J. F., Hong, S. H., Toth, E. D., Nguyễn, T. T., & Arora, P. S. (2025) · Angewandte Chemie · doi:10.1002/ange.202507092
Cyclic Peptides for PPI Drug Discovery
Hu, H., & Li, X. (2025) · doi:10.1002/9783527845828.ch11
Liu, J., Yang, J., Pan, Q., Wang, X., Wang, X., Chen, H., Zheng, X., & Huang, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26673561
Pektaş, S. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-12535-x
Aydın, G., Aysan, A., Duyar, C., Şenkuytu, E., Doğancı, M. D., Doğancı, E., & Davarcı, D. (2026) · Inorganic Chemistry Communications · doi:10.1016/j.inoche.2026.117514
BindingDB Entry 50001421: Artificial Macrocycles as Potent p53-MDM2 Inhibitors.
BindingDB (2020) · UC San Diego · doi:10.7270/q2tq6424
Metadata
- Authors
- Phan, J., Li, Z., Kasprzak, A., Li, B., Sebti, S., Guida, W., Schönbrunn, E., & Chen, J.
- Affiliations
- Moffitt Cancer Center (US)
- University of South Florida (US)
- Corresponding author
- Schönbrunn, Ernst
- Chen, Jiandong
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 285
- Issue
- 3
- Pages
- 2174-2183
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2804373
- OpenAlex
- W2109871942
- Cited by
- 173
- References
- 43
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 12 · 2023: 7 · 2022: 12 · 2021: 8 · 2020: 10 · 2019: 11 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 13 · 2014: 10 · 2013: 7 · 2012: 15
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA109636, CA 109636, CA 118210, P01CA118210)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- p53, MDM2, MDMX, peptide inhibitors, structure-based peptide design, p53-MDM2 interaction, phage display, co-crystal structure, hydrophobic binding site, conformational change, p53 activation, small molecule inhibitors
- MeSH terms
- Amino Acid Sequence, Animals, Enzyme Inhibitors, Humans, Models, Molecular, Mutation, Oligopeptides, Protein Binding, Substrate Specificity, Drug Design, Tumor Suppressor Protein p53, Protein Structure, Secondary, Crystallography, X-Ray, Mice, Proto-Oncogene Proteins c-mdm2
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