ArticleProtein engineering, design & selection : PEDS2009
Stabilising the DNA-binding domain of p53 by rational design of its hydrophobic core.
Article in Protein engineering, design & selection : PEDS, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 23 citations in OpenAlex.
- Cancer-linked aggregation of p53 is driven by sequence-encoded frustration, solvation, and hydrophobic gating absent in its paralogs.Communications chemistry · 2026Article
- Structural diversity of p63 and p73 isoforms.Cell death and differentiation · 2022Review
- Evolutionary history of the p53 family DNA-binding domain: insights from an Alvinella pompejana homolog.Cell death & disease · 2022Article
- Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.PloS one · 2017Article
- Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds.Scientific reports · 2016Article
- XPA: A key scaffold for human nucleotide excision repair.DNA repair · 2016Review
- Solution structure and binding specificity of the p63 DNA binding domain.Scientific reports · 2016Article
- Are all regions of folded proteins that undergo ligand-dependent order-disorder transitions targets for allosteric peptide mimetics?Biopolymers · 2013Article
- A single mutant, A276S of p53, turns the switch to apoptosis.Molecular pharmaceutics · 2013Article
- Tracing the protectors path from the germ line to the genome.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- The tumor suppressor p53: from structures to drug discovery.Cold Spring Harbor perspectives in biology · 2010Review
- Effects of stability on the biological function of p53.The Journal of biological chemistry · 2009Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
The core domain of the tumour suppressor p53 is of inherently low thermodynamic stability and also low kinetic stability, which leads to rapid irreversible denaturation. Some oncogenic mutations of p53 act by just making the core domain thermosensitive, and so it is the target of novel anti-cancer drugs that bind to and stabilise the protein. Increasing the stability of the unstable core domain has also been crucial for biophysical and structural studies, in which a stabilised quadruple mutant (QM) is currently used. We generated an even more stabilised hexamutant (HM) by making two additional substitutions, Y236F and T253I, to the QM. The residues are found in the more stable paralogs p63 and p73 and stabilise the wild-type p53 core domain. We solved the structure of the HM core domain by X-ray crystallography at 1.75 A resolution. It has minimal structural changes from QM that affect the packing of hydrophobic core residues of the beta-sandwich. The full-length HM was also fully functional in DNA binding. HM was more stable than QM at 37 degrees C. Anomalies in biophysics and spectroscopy in urea-mediated denaturation curves of HM implied the accumulation of a folding intermediate, which may be related to those detected in kinetic experiments. The two additional mutations over-stabilise an unfolding intermediate. These results should be taken into consideration in drug design strategies for increasing the stability of temperature-sensitive mutants of p53.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.