ArticleProtein science : a publication of the Protein Society2010
Stabilization of mutant p53 via alkylation of cysteines and effects on DNA binding.
Article in Protein science : a publication of the Protein Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 74 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Covalent drug rescue of multiple p53 mutants by stabilizing vinyl sulfone fragments hints to a specific refolding mechanism for R282W.Protein science : a publication of the Protein Society · 2026Article
- Discovery of novel covalent stabilizers for p53 Y220C using structure-based drug discovery methods.Molecular diversity · 2025Article
- Design, Synthesis, and Molecular Evaluation of SArchiv der Pharmazie · 2025Article
- Mechanistic Insights of a p53-Targeting Small Molecule.ACS pharmacology & translational science · 2025Article
- Deciphering the safeguarding role of cysteine residues in p53 against HCommunications chemistry · 2025Article
- SDrug design, development and therapy · 2025Article
- Screening of Covalent Kinase Inhibitors Yields Hits for Cysteine Protease USP7 / HAUSP.Drug design, development and therapy · 2025Article
- Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution.ACS pharmacology & translational science · 2024Article
- From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.Biomarker research · 2024Review
- Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy.Cancer communications (London, England) · 2024Review
- Evaluation of a Covalent Library of Diverse Warheads (CovLib) Binding to JNK3, USP7, or p53.Drug design, development and therapy · 2024Article
- TRAP1 S-nitrosylation as a model of population-shift mechanism to study the effects of nitric oxide on redox-sensitive oncoproteins.Cell death & disease · 2023Article
- Revisiting a challenging p53 binding site: a diversity-optimized HEFLib reveals diverse binding modes in T-p53C-Y220C.RSC medicinal chemistry · 2022Article
- Anticancer Therapeutic Strategies Targeting p53 Aggregation.International journal of molecular sciences · 2022Review
- BAP1 phosphorylation-mediated Sp1 stabilization plays a critical role in cathepsin K inhibition-induced C-terminal p53-dependent Bax upregulation.Redox biology · 2022Article
- Nitrogen Mustard Alkylates and Cross-Links p53 in Human Keratinocytes.Chemical research in toxicology · 2022Article
- Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer.Biomolecules · 2022Review
- Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ).Nature communications · 2021Article
- Redox Sensitive Cysteine Residues as Crucial Regulators of Wild-Type and Mutant p53 Isoforms.Cells · 2021Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Oncogenic mutations inactivate the tumor suppressor p53 by lowering its stability or by weakening its binding to DNA. Alkylating agents that reactivate mutant p53 are currently being explored for cancer therapy. We have discovered ligands containing an α,β-unsaturated double bond, characteristic of Michael acceptors, that bind covalently to generic cysteine sites in the p53 core domain. They raised the melting temperature of the core domain of wild-type p53 and the hotspot mutants R175H, Y220C, G245S, R249S, and R282 by up to 3°C. Analysis of the relative reactivity of the cysteines in p53 by mass spectrometry found that C124 and C141 react first, followed by C135, C182, and C277, and eventually C176 and C275. Post-translational modifications of cysteines are known to be involved in regulation of other transcription factors. Modification of C277, which sits on the DNA-binding surface, may, for example, play a role in regulating p53 activity in cells in response to environmental cues. We found that the modifications progressively reduced DNA-binding activity of full-length p53. In light of these results, it is likely that the anticancer activity of the alkylating drugs works via a nontranscriptional activity of p53.
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Registered trials
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.