The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Structural basis for understanding oncogenic p53 mutations and designing rescue drugs
Open accessAbstract
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.
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Self-citationSolution structure of p53 core domain: Structural basis for its instability
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Metadata
- Authors
- Joerger, A. C., Ang, H. C., & Fersht, A. R.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2006-10-10
- Volume
- 103
- Issue
- 41
- Pages
- 15056-15061
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2072052957
- Cited by
- 353
- References
- 8
- FWCI
- 6.51
- Type
- journal article
- Language
- en
- Open access
- green
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