The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Targeted rescue of a destabilized mutant of p53 by an in silico screened drug
Open accessAbstract
The tumor suppressor p53 is mutationally inactivated in ≈50% of human cancers. Approximately one-third of the mutations lower the melting temperature of the protein, leading to its rapid denaturation. Small molecules that bind to those mutants and stabilize them could be effective anticancer drugs. The mutation Y220C, which occurs in ≈75,000 new cancer cases per annum, creates a surface cavity that destabilizes the protein by 4 kcal/mol, at a site that is not functional. We have designed a series of binding molecules from an in silico analysis of the crystal structure using virtual screening and rational drug design. One of them, a carbazole derivative (PhiKan083), binds to the cavity with a dissociation constant of ≈150 μM. It raises the melting temperature of the mutant and slows down its rate of denaturation. We have solved the crystal structure of the protein–PhiKan083 complex at 1.5-Å resolution. The structure implicates key interactions between the protein and ligand and conformational changes that occur on binding, which will provide a basis for lead optimization. The Y220C mutant is an excellent “druggable” target for developing and testing novel anticancer drugs based on protein stabilization. We point out some general principles in relationships between binding constants, raising of melting temperatures, and increase of protein half-lives by stabilizing ligands.
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“Several small molecules have been shown to bind to the hydrophobic pocket of Y220C and restore p53 function467–478”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [467]
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“For example, a special class of p53 structural mutant, Y220C, leads to a hydrophobic cavity in p53 protein structure.467”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [467]
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Solution structure of p53 core domain: Structural basis for its instability
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Cited by
Apoptosis in cancer: from pathogenesis to treatment
Wong, R. S. (2011) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-30-87 · Cited by 2,836
TP53 mutations in human cancers: origins, consequences, and clinical use.
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The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967
Kastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906
Muller, P. A. J., & Vousden, K. H. (2013) · Nature Cell Biology · doi:10.1038/ncb2641 · Cited by 1,647
Metadata
- Authors
- Boeckler, F. M., Joerger, A. C., Jaggi, G., Rutherford, T. J., Veprintsev, D. B., & Fersht, A. R.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2008-07-29
- Volume
- 105
- Issue
- 30
- Pages
- 10360-10365
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2110947069
- Cited by
- 387
- References
- 8
- FWCI
- 10.16
- Type
- journal article
- Language
- en
- Open access
- green
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- Boeckler, F. M., Joerger, A. C., Jaggi, G., Rutherford, T. J., Veprintsev, D. B., & Fersht, A. R. (2008). Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0805326105
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