A peptide that binds and stabilizes p53 core domain: Chaperone strategy for rescue of oncogenic mutants
| Autor: | Mark R. Proctor, Thomas M Rippin, Lars O. Hansson, Penka V. Nikolova, Assaf Friedler, Alan R. Fersht, Dmitry B. Veprintsev, Stefan M.V. Freund, Stefan G.D. Rüdiger |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular Protein Folding Molecular Sequence Data Plasma protein binding In Vitro Techniques Biology Binding Competitive Drug Stability Native state Humans Amino Acid Sequence Binding site Peptide sequence Binding Sites Multidisciplinary Base Sequence DNA Biological Sciences Peptide Fragments Protein Structure Tertiary DNA binding site Biochemistry Chaperone (protein) Mutation biology.protein Biophysics Tumor Suppressor Protein p53 Oligopeptides Molecular Chaperones Protein Binding P53 binding Binding domain |
| Zdroj: | Proceedings of the National Academy of Sciences. 99:937-942 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.241629998 |
| Popis: | Conformationally compromised oncogenic mutants of the tumor suppressor protein p53 can, in principle, be rescued by small molecules that bind the native, but not the denatured state. We describe a strategy for the rational search for such molecules. A nine-residue peptide, CDB3, which was derived from a p53 binding protein, binds to p53 core domain and stabilizes it in vitro . NMR studies showed that CDB3 bound to p53 at the edge of the DNA binding site, partly overlapping it. The fluorescein-labeled peptide, FL-CDB3, binds wild-type p53 core domain with a dissociation constant of 0.5 μM, and raises the apparent melting temperatures of wild-type and a representative oncogenic mutant, R249S core domain. gadd45 DNA competes with CDB3 and displaces it from its binding site. But this competition does not preclude CDB3 from being a lead compound. CDB3 may act as a “chaperone” that maintains existing or newly synthesized destabilized p53 mutants in a native conformation and then allows transfer to specific DNA, which binds more tightly. Indeed, CDB3 restored specific DNA binding activity to a highly destabilized mutant I195T to close to that of wild-type level. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|