Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.

Article Details

Citation

Joerger AC, Ang HC, Fersht AR

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. Epub 2006 Oct 2.

PubMed ID
17015838 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cellular tumor antigen p53P04637Details