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

Joerger AC, Ang HC, Fersht AR
Proc Natl Acad Sci U S A 103 15056-61 (2006)
Related entries: 1uol, 2bim, 2bin, 2bio, 2bip, 2biq, 2j1w, 2j1x, 2j1z, 2j20, 2j21

Cited: 190 times
EuropePMC logo PMID: 17015838

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.

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  1. Structural and Drug Targeting Insights on Mutant p53. Gomes AS, Ramos H, Inga A, Sousa E, Saraiva L. Cancers (Basel) 13 3344 (2021)

Articles - 2j1y mentioned but not cited (5)

  1. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Joerger AC, Ang HC, Fersht AR. Proc Natl Acad Sci U S A 103 15056-15061 (2006)
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Reviews citing this publication (52)

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