Structure of the Tetrameric p53 Tumor Suppressor Bound to DNA
Annual rept. 15 Apr 2000-14 Apr 2001
PENNSYLVANIA UNIV PHILADELPHIA WISTAR INST
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The p53 transcriptional activator binds DNA as a tetramer to activate the transcription of genes involved in cell cycle arrest and apoptosis, and alterations in the DNA-binding core domain of p53 are the most common genetic changes found in breast cancer. The overall goal of this proposal is to determine the X-ray crystal structure of a tetrameric form of p53 bound to DNA. Over the last year we determined the structure of the core domain of p53 in the absence of DNA and have described the results of this work in the Journal of Biological Chemistry. We have also made progress towards the structure determination of a tetrameric form of p53 bound to DNA. Specifically, we have overexpressed in bacteria two relevant protein constructs of p53 that are competent for tetramer formation on DNA p5386-391, and full-length p53. We have purified the p5386-391 construct to homogeneity and cocrystallization efforts with DNA for structure determination are underway. The structure of tetrameric p53 bound to DNA will provide mechanistic insights into the structural basis underlying p53 mutations, and will provide a framework for the structure-based design of drugs that will be useful in the treatment of p53-mediated breast cancer.
- Medicine and Medical Research