Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.
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.
Joerger
Andreas C
AC
Cambridge University Chemical Laboratory and Cambridge Centre for Protein Engineering, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom.
Ang
Hwee Ching
HC
Fersht
Alan R
AR
D019943:Amino Acid Substitution / Q000235:genetics; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009857:Oncogenes; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53