Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy

Oncogene. 2000 Mar 2;19(10):1245-56. doi: 10.1038/sj.onc.1203434.


The tumour suppressor p53 is mutated in half of all human cancers, most frequently with missense substitutions in its core domain. We present a new assessment of the mutation database based on quantitative folding and DNA-binding studies of the isolated core domain. Our data identify five distinct mutant classes that correlate with four well-defined regions of the core domain structure. On extrapolation to 37 degrees C the wild-type protein has a stability of 3.0 kcal/mol. This also emerges as an oncogenic threshold: all beta-sandwich mutants destabilized by this amount (50% denatured) are expected to promote cancer. Other weakly destabilizing mutations are restricted to loop 3 in the DNA-binding region. Drugs that stabilize mutant p53 folding have the potential to reactivate apoptotic signalling pathways in tumour cells either by transactivation-dependent or independent pathways. Using an affinity ligand as a proof of principle we have recovered the thermodynamic stability of the hotspot G245S. With reference states for the five mutant classes as a guide, future therapeutic strategies may similarly stabilize partially structured or binding states of mutant p53 that restore limited p53 pathways to tumour suppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Databases, Factual
  • Genes, p53*
  • Humans
  • Models, Chemical
  • Models, Molecular
  • Mutation*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Protein Denaturation
  • Protein Folding*
  • Recombinant Proteins / chemistry
  • Spectrometry, Fluorescence
  • Temperature
  • Thermodynamics
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / chemistry*


  • Peptide Fragments
  • Recombinant Proteins
  • Tumor Suppressor Protein p53