Recent studies suggest that p53 binds predominantly to consensus sites composed of two decameric half-sites with zero spacing in vivo. Here we report the crystal structure of the p53 core domain bound to a full consensus site as a tetramer at 2.13Å resolution. Comparison with previously reported structures of p53 dimer:DNA complexes and a chemically trapped p53 tetramer:DNA complex reveals that DNA binding by the p53 core domain is a cooperative self-assembling process accompanied by structural changes of the p53 dimer and DNA. Each p53 monomer interacts with its two neighboring subunits through two different protein-protein interfaces. The DNA is largely B-form and shows no discernible bend, but the central base-pairs between the two half-sites display a significant slide. The extensive protein-protein and protein-DNA interactions explain the high cooperativity and kinetic stability of p53 binding to contiguous decameric sites and the conservation of such binding-site configuration in vivo.
Bibliographical noteFunding Information:
The authors would like to thank Xiaojiang Chen for providing the expression vector of the human p53 core domain and for helpful discussion, and James C. Stroud for help with DNA structural analysis, Michael Philips for proof reading the manuscript. The authors would also like to thank ALS BCSB staff members Corie Ralston, Peter Zwart, and Kevin Royal for help with data collection. This work is supported by a NIH postdoctoral fellowship to Y. C. and NIH grants to L.C.