Structural basis for p53 binding-induced DNA bending

J Biol Chem. 2007 Jan 5;282(1):691-9. doi: 10.1074/jbc.M605908200. Epub 2006 Nov 3.

Abstract

Specific p53 binding-induced DNA bending has important biological implications such as transcription activation. However, the detailed structures of the bent DNA and the p53-DNA complex are still unavailable, hampering our understanding of the mechanism for p53-induced DNA bending and its consequent biological significance. To gain insight into the p53 binding-induced DNA bending, we performed molecular dynamics simulations on DNA segments with the consensus sequence for p53-specific binding, half site DNA-p53 complexes, and full site DNA-p53 complexes. We show that each DNA-bound p53 core domain caused a local DNA conformational change within the quarter site; upon the binding of the p53 dimer, there was an apparent DNA bending at the center of the half site; when bound with two p53 dimers, the full site DNAs with two different sequences bent 20 and 35 degrees, respectively. These results are in agreement with experimental observations. Our simulations demonstrate that the two p53 dimers favored a staggered conformation in which they make favorable interactions at the interface. This dimer-dimer interface organization necessitated conformational changes in the DNA, leading to the bending at the center of the full site, which in turn is dependent on the DNA sequence. Overall, our results provide the detailed atomic model for the DNA-p53 tetramer complex and delineate the roles of DNA-p53, p53 dimer-dimer interactions, and DNA sequence in specific p53 binding-induced DNA conformational changes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • DNA / chemistry*
  • DNA-Binding Proteins / chemistry
  • Dimerization
  • Genes, p53
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Nucleic Acid Conformation
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • DNA