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

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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, Zella, Davide, Tarasov, Sergey G., Lu, Wuyuan·2009·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0900947106PMC PMC2660734

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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)
ORCID: Pazgier, Marzena
Liu, Min
Zou, Guozhang
Li, Changqing
Li, Chong
Li, Jing
Zella, Davide
Tarasov, Sergey G.
Lu, Wuyuan
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2009-03-24
Volume: 106
Issue: 12
Pages: 4665-4670
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0900947106
PMC: PMC2660734
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: green
www.ncbi.nlm.nih.gov
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
Physical Sciences › Chemistry › Organic Chemistry › 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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Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX

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