Structure of the Tetrameric p53 Tumor Suppressor Bound to DNA

摘要

The p53 tumor suppressor binds DNA as a tetramer to regulate 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 goal of this proposal was to determine the X-ray crystal structure of a p53 tetramer bound to DNA. Towards this goal, we successfully prepared several p53 and short duplex DNA reagents, but have been unable to prepare suitable p53/DNA cocrystals for structure determination. Nonetheless, we have successfully determined the medium resolution (2.7A) structure of the nascent p53 core domain which we reported in the Journal of Biological Chemistry, and have more recently obtained crystal of the p53 core domain that will yield a structure to 2.2A resolution. Future efforts to obtain a structure of the p53 tetramer bound to DNA will involve cocrystallization with longer DNA targets or DNA targets assembled into nucleosome core particles. The structure of tetrameric p53 bound to DNA will provide new 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.