Structural Basis for Understanding Oncogenic p53 Mutations and Designing Rescue Drugs

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-10, Vol.103 (41), p.15056-15061
• Main Authors: Joerger, Andreas C., Ang, Hwee Ching, Fersht, Alan R.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution - genetics; Antineoplastic Agents - chemical synthesis; Atoms; Biological Sciences; Cancer; Crystal structure; Crystallography, X-Ray; Crystals; Deoxyribonucleic acid; DNA; Drug Design; Drugs; Genetic mutation; Humans; Molecular structure; Molecules; Mutagenesis, Site-Directed; Mutation; Oncogenes; Polymorphism; Proteins; Studies; Thermodynamics; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0607286103

The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in ≈ 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.