Small-molecule stabilization of the p53 - 14-3-3 protein-protein interaction
| Autor: | Qing Cao, Richard G. Doveston, Seppe Leysen, Maria Paola Castaldi, Helen Boyd, Sebastian A. Andrei, Hongming Chen, Luc Brunsveld, Christian Ottmann, J. Adam Hendricks, Ave Kuusk |
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| Přispěvatelé: | Chemical Biology |
| Rok vydání: | 2017 |
| Předmět: |
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Molecular p53 0301 basic medicine Letter Chemie Biophysics Crystallographic data fluorescence polarization SDG 3 – Goede gezondheid en welzijn Bioinformatics medicine.disease_cause Biochemistry Protein Structure Secondary law.invention Negative regulator 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being Structural Biology law protein crystallography Genetics medicine Glycosides Molecular Biology 14-3-3 protein PPI stabilization Mutation biology Protein Stability Chemistry 14-3-3 proteins Cell Biology Small molecule isothermal titration calorimetry Cell biology 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Suppressor Mdm2 Tumor Suppressor Protein p53 Function (biology) Protein Binding |
| Zdroj: | FEBS Letters, 591(16), 2449-2457. Elsevier FEBS Letters |
| ISSN: | 0014-5793 |
| DOI: | 10.1002/1873-3468.12723 |
| Popis: | 14-3-3 proteins are positive regulators of the tumor suppressor p53, the mutation of which is implicated in many human cancers. Current strategies for targeting of p53 involve restoration of wild-type function or inhibition of the interaction with MDM2, its key negative regulator. Despite the efficacy of these strategies, the alternate approach of stabilizing the interaction of p53 with positive regulators and, thus, enhancing tumor suppressor activity, has not been explored. Here, we report the first example of small-molecule stabilization of the 14-3-3 - p53 protein-protein interaction (PPI) and demonstrate the potential of this approach as a therapeutic modality. We also observed a disconnect between biophysical and crystallographic data in the presence of a stabilizing molecule, which is unusual in 14-3-3 PPIs. |
| Databáze: | OpenAIRE |
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