DOI: 10.1073/pnas.0900947106. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX

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

10.1073/pnas.0900947106

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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.

Bibliography

Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., & Lu, W. (2009). Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proceedings of the National Academy of Sciences, 106(12), 4665â4670.

Authors 11

Marzena Pazgier (first)
Min Liu (additional)
Guozhang Zou (additional)
Weirong Yuan (additional)
Changqing Li (additional)
Chong Li (additional)
Jing Li (additional)
Juahdi Monbo (additional)
Davide Zella (additional)
Sergey G. Tarasov (additional)
Wuyuan Lu (additional)

References 51 Referenced 346

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Dates

Type	When
Created	16 years, 5 months ago (March 2, 2009, 9:43 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 5:35 p.m.)
Indexed	2 days, 21 hours ago (Aug. 22, 2025, 12:48 a.m.)
Issued	16 years, 5 months ago (March 24, 2009)
Published	16 years, 5 months ago (March 24, 2009)
Published Online	16 years, 5 months ago (March 24, 2009)
Published Print	16 years, 5 months ago (March 24, 2009)

Funders 0

None

BibTeX

@article{Pazgier_2009, title={Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX}, volume={106}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0900947106}, DOI={10.1073/pnas.0900947106}, number={12}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Pazgier, Marzena and Liu, Min and Zou, Guozhang and Yuan, Weirong and Li, Changqing and Li, Chong and Li, Jing and Monbo, Juahdi and Zella, Davide and Tarasov, Sergey G. and Lu, Wuyuan}, year={2009}, month=mar, pages={4665–4670} }

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      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}