Cited by 179Cancer-related Molecular PathwaysProtein Structure and DynamicsChemical Synthesis and Analysis

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Structure-based Design of High Affinity Peptides Inhibiting the Interaction of p53 with MDM2 and MDMX

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Phan, Jason, Li, Zhenyu, Kasprzak, Agnieszka, Li, Baozong, Sebti, Said, Guida, Wayne, Schönbrunn, Ernst, Chen, Jiandong·2010·Journal of Biological Chemistry

DOI 10.1074/jbc.m109.073056PMC PMC2804373

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Abstract

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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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
Improved methods for building protein models in electron density maps and the location of errors in these models
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

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Chen, 1993, Mol. Cell. Biol., 13, 4107

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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
ORCID: Li, Zhenyu
Guida, Wayne
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)
DOI: 10.1074/jbc.m109.073056
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 3946 d)
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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Structure-based Design of High Affinity Peptides Inhibiting the Interaction of p53 with MDM2 and MDMX

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