Structural basis for understanding oncogenic p53 mutations and designing rescue drugs

Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15056-61. doi: 10.1073/pnas.0607286103. Epub 2006 Oct 2.


The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Antineoplastic Agents / chemical synthesis*
  • Crystallography, X-Ray
  • Drug Design*
  • Humans
  • Mutagenesis, Site-Directed*
  • Oncogenes*
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / genetics*


  • Antineoplastic Agents
  • Tumor Suppressor Protein p53

Associated data

  • PDB/2J1W
  • PDB/2J1X
  • PDB/2J1Y
  • PDB/2J1Z
  • PDB/2J20
  • PDB/2J21