Structure of the Tetrarneric p53 Tumor Supressor Bound to DNA
Annual rept. 15 Apr 1999-14 Apr 2000
PENNSYLVANIA UNIV PHILADELPHIA WISTAR INST
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The p53 transcriptional activator binds to DNA as a tetramer to activate the transcription of genes involved in cell cycle arrest and apoptosis, and alterations in the DNA-binding domain of p53 are the most common genetic changes found to date in breast cancer. The overall goal of the proposal is to determine the X-ray crystal structure of tetrameric forms of p53 bound to DNA. Over the last year we have made significant progress towards achieving this goal. Specifically, we have successfully cloned, overexpressed and purified to homogeneity two relevant protein constructs of p53 that are competent for tetramer formation on DNA p5398-292, and p5386-35 1. We are pursuing the structure determination of both of these protein constructs bound to DNA in parallel. For the p5398-292 protein construct we have obtained crystals of a p53DNA complex and a structure determination is in progress, and for the p5386-35l construct cocrystallization trials with DNA are in progress. The structure of these p53DNA complexes will provide a mechanistic understanding 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.
- Anatomy and Physiology
- Medicine and Medical Research