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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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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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