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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Crystal Structure of a p53 Tumor Suppressor-DNA Complex: Understanding Tumorigenic Mutations
Cho, Y., Gorina, S., Jeffrey, P. D., & Pavletich, N. P. (1994) · Science · doi:10.1126/science.8023157 · Cited by 2,551
The IARC TP53 database: new online mutation analysis and recommendations to users
Olivier, M., Eeles, R., Hollstein, M., Khan, M. A., Harris, C. C., & Hainaut, P. (2002) · Human Mutation · doi:10.1002/humu.10081 · Cited by 1,248
Hot-spot mutants of p53 core domain evince characteristic local structural changes
Wong, K.-B., DeDecker, B. S., Freund, S. M. V., Proctor, M. R., Bycroft, M., & Fersht, A. R. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.15.8438 · Cited by 221
Self-citationSolution structure of p53 core domain: Structural basis for its instability
Cañadillas, J. M. P., Tidow, H., Freund, S. M. V., Rutherford, T. J., Ang, H. C., & Fersht, A. R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510941103 · Cited by 174
Self-citationCore domain interactions in full-length p53 in solution
Veprintsev, D. B., Freund, S. M. V., Andreeva, A., Rutledge, S. E., Tidow, H., Cañadillas, J. M. P., Blair, C. M., & Fersht, A. R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0511130103 · Cited by 95
Self-citationMenendez, D., Inga, A., & Resnick, M. A. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.6.2297-2308.2006 · Cited by 81
Cited by
TP53 mutations in human cancers: origins, consequences, and clinical use.
Olivier, M., Hollstein, M., & Hainaut, P. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001008 · Cited by 2,199
mCSM: Predicting the effects of mutations in proteins using graph-based signatures
Pires, D. E. V., Ascher, D. B., & Blundell, T. L. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btt691 · Cited by 1,066
Targeting mutant p53 for efficient cancer therapy
Bykov, V. J. N., Eriksson, S. E., Bianchi, J., & Wiman, K. G. (2018) · Nature Reviews Cancer · doi:10.1038/nrc.2017.109 · Cited by 889
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881
Self-citationTP53 mutations in human cancers: Functional selection and impact on cancer prognosis and outcomes
Petitjean, A., Achatz, M. I. W., Borresen-Dale, A. L., Hainaut, P., & Olivier, M. (2007) · Oncogene · doi:10.1038/sj.onc.1210302 · Cited by 884
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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