Structural basis for understanding oncogenic p53 mutations and designing rescue drugs

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Abstract

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. © 2006 by The National Academy of Sciences of the USA.

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Joerger, A. C., Ang, H. C., & Fersht, A. R. (2006). Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proceedings of the National Academy of Sciences of the United States of America, 103(41), 15056–15061. https://doi.org/10.1073/pnas.0607286103

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