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A Peptide That Binds and Stabilizes p53 Core Domain: Chaperone Strategy for Rescue of Oncogenic Mutants
Assaf Friedler, Lars O. Hansson, Dmitry B. Veprintsev, Stefan M. V. Freund, Thomas M. Rippin, Penka V. Nikolova, Mark R. Proctor, Stefan Rüdiger and Alan R. Fersht
Proceedings of the National Academy of Sciences of the United States of America
Vol. 99, No. 2 (Jan. 22, 2002), pp. 937-942
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3057669
Page Count: 6
You can always find the topics here!Topics: DNA, Anisotropy, Binding sites, Genetic mutation, Fluorescence, Molecules, Protein refolding, Chemical equilibrium, Color semiotics, Standard deviation
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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.
Proceedings of the National Academy of Sciences of the United States of America © 2002 National Academy of Sciences