Cited by 403Cancer-related Molecular PathwaysProtein Structure and DynamicsChemical Synthesis and Analysis

Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX

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Pazgier, Marzena, Liu, Min, Zou, Guozhang, Yuan, Weirong, Li, Changqing, Li, Chong, Li, Jing, Monbo, Juahdi +3 more·2009·Proceedings of the National Academy of Sciences

Abstract

The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53—a cellular process initiated by MDM2 and/or MDMX binding to the N-terminal transactivation domain of p53. MDM2 and MDMX in many tumors confer p53 inactivation and tumor survival, and are important molecular targets for anticancer therapy. We screened a duodecimal peptide phage library against site-specifically biotinylated p53-binding domains of human MDM2 and MDMX chemically synthesized via native chemical ligation, and identified several peptide inhibitors of the p53-MDM2/MDMX interactions. The most potent inhibitor (TSFAEYWNLLSP), termed PMI, bound to MDM2 and MDMX at low nanomolar affinities—approximately 2 orders of magnitude stronger than the wild-type p53 peptide of the same length (ETFSDLWKLLPE). We solved the crystal structures of synthetic MDM2 and MDMX, both in complex with PMI, at 1.6 Å resolution. Comparative structural analysis identified an extensive, tightened intramolecular H-bonding network in bound PMI that contributed to its conformational stability, thus enhanced binding to the 2 oncogenic proteins. Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX. Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use.

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Authors
Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., & Lu, W.
Affiliations
  • University of Maryland, Baltimore (US)
  • National Cancer Institute (US)
Venue
Proceedings of the National Academy of Sciences
Published
2009-03-24
Volume
106
Issue
12
Pages
4665-4670
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2076060796
Cited by
391
References
53
Citations by year
2026: 10 · 2025: 28 · 2024: 27 · 2023: 23 · 2022: 18 · 2021: 29 · 2020: 25 · 2019: 24 · 2018: 18 · 2017: 31 · 2016: 18 · 2015: 20 · 2014: 24 · 2013: 21 · 2012: 19
FWCI
12.67
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (AI056264)
  • National Institute of Allergy and Infectious Diseases (AI 061482, AI 056264, R21AI056264, R01AI061482)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords
p53, MDM2, MDMX, peptide inhibitors, transactivation domain, crystal structure, hydrogen bond network, hydrophobic cleft, p53 activators, anticancer drug design, phage display peptide library, native chemical ligation
MeSH terms
Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Oligopeptides, Peptides, Protein Binding, Proto-Oncogene Proteins, Structure-Activity Relationship, Tumor Suppressor Protein p53, Protein Structure, Secondary, Cell Cycle Proteins, Peptide Library, Proto-Oncogene Proteins c-mdm2

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