Structural basis of DNA recognition by p53 tetramers

Mol Cell. 2006 Jun 23;22(6):741-53. doi: 10.1016/j.molcel.2006.05.015.


The tumor-suppressor protein p53 is among the most effective of the cell's natural defenses against cancer. In response to cellular stress, p53 binds as a tetramer to diverse DNA targets containing two decameric half-sites, thereby activating the expression of genes involved in cell-cycle arrest or apoptosis. Here we present high-resolution crystal structures of sequence-specific complexes between the core domain of human p53 and different DNA half-sites. In all structures, four p53 molecules self-assemble on two DNA half-sites to form a tetramer that is a dimer of dimers, stabilized by protein-protein and base-stacking interactions. The protein-DNA interface varies as a function of the specific base sequence in correlation with the measured binding affinities of the complexes. The new data establish a structural framework for understanding the mechanisms of specificity, affinity, and cooperativity of DNA binding by p53 and suggest a model for its regulation by regions outside the sequence-specific DNA binding domain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Binding Sites
  • Cell Cycle
  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA / metabolism
  • Gene Expression Regulation, Neoplastic
  • Models, Molecular*
  • Neoplasms / metabolism
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / metabolism


  • Tumor Suppressor Protein p53
  • DNA

Associated data

  • PDB/2AC0
  • PDB/2ADY
  • PDB/2AHI
  • PDB/2ATA