Structure of the Tetrarneric p53 Tumor Supressor Bound to DNA
Abstract
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; p53(98-292), and p53(86-35 1). We are pursuing the structure determination of both of these protein constructs bound to DNA in parallel. For the p53(98-292) protein construct we have obtained crystals of a p53/DNA complex and a structure determination is in progress, and for the p53(86-35l) construct cocrystallization trials with DNA are in progress. The structure of these p53/DNA 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2000
- Accession Number
- ADA383177
Entities
People
- Ronen Marmorstein
Organizations
- University of Pennsylvania