Structure of the Stapled p53 Peptide Bound to Mdm2
Open accessAbstract
Mdm2 is a major negative regulator of the tumor suppressor p53 protein, a protein that plays a crucial role in maintaining genome integrity. Inactivation of p53 is the most prevalent defect in human cancers. Inhibitors of the Mdm2-p53 interaction that restore the functional p53 constitute potential nongenotoxic anticancer agents with a novel mode of action. We present here a 2.0 Å resolution structure of the Mdm2 protein with a bound stapled p53 peptide. Such peptides, which are conformationally and proteolytically stabilized with all-hydrocarbon staples, are an emerging class of biologics that are capable of disrupting protein-protein interactions and thus have broad therapeutic potential. The structure represents the first crystal structure of an i, i + 7 stapled peptide bound to its target and reveals that rather than acting solely as a passive conformational brace, a staple can intimately interact with the surface of a protein and augment the binding interface.
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- Authors
- Baek, S., Kutchukian, P. S., Verdine, G. L., Huber, R., Holak, T. A., Lee, K. W., & Popowicz, G. M.
- Affiliations
- Seoul National University (KR)
- Harvard University (US)
- Max Planck Society (DE)
- Jagiellonian University (PL)
- Corresponding author
- Popowicz, Grzegorz M.
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-12-14
- Volume
- 134
- Issue
- 1
- Pages
- 103-106
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W1971495173
- Cited by
- 259
- References
- 26
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 8 · 2023: 15 · 2022: 15 · 2021: 18 · 2020: 18 · 2019: 18 · 2018: 11 · 2017: 27 · 2016: 30 · 2015: 18 · 2014: 24 · 2013: 23 · 2012: 11
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- green
- ruj.uj.edu.pl
- Licence
- cc-by-nc-nd
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- MDM2, p53, stapled peptides, protein-protein interaction inhibition, crystal structure, tumor suppressor, anticancer agents, binding interface
- MeSH terms
- Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Protein Binding, Tumor Suppressor Protein p53, Protein Structure, Secondary, Crystallography, X-Ray, Proto-Oncogene Proteins c-mdm2
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