ArticleThe Journal of biological chemistry2017
Conformational dynamics of the TTD-PHD histone reader module of the UHRF1 epigenetic regulator reveals multiple histone-binding states, allosteric regulation, and druggability.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Article
- UHRF1 as an epigenetic therapeutic target in Cancer.Molecular biology reports · 2026Review
- Molecular Mechanisms of Biochanin A in AML Cells: Apoptosis Induction and Pathway-Specific Regulation in U937 and THP-1.International journal of molecular sciences · 2025Article
- Negative Cooperativity in the UHRF1 TTD-PHD Dual Domain Masks the Contributions of Cation-π Interactions between Trimethyllysine and the TTD Aromatic Cage.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Defining ortholog-specific UHRF1 inhibition by STELLA for cancer therapy.Nature communications · 2025Article
- Deciphering the dual roles of PHD finger proteins from oncogenic drivers to tumor suppressors.Frontiers in cell and developmental biology · 2024Review
- Refined read-out: The hUHRF1 Tandem-Tudor domain prefers binding to histone H3 tails containing K4me1 in the context of H3K9me2/3.Protein science : a publication of the Protein Society · 2023Article
- Natural and Synthetic Anticancer Epidrugs Targeting the Epigenetic Integrator UHRF1.Molecules (Basel, Switzerland) · 2023Review
- Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia.Cell research · 2022Article
- Molecular basis of hUHRF1 allosteric activation for synergistic histone modification binding by PI5P.Science advances · 2022Article
- Discovery and Mechanism of Small Molecule Inhibitors Selective for the Chromatin-Binding Domains of Oncogenic UHRF1.Biochemistry · 2022Article
- 5-methylcytosine turnover: Mechanisms and therapeutic implications in cancer.Frontiers in molecular biosciences · 2022Review
- Inhibitors of DNA Methylation.Advances in experimental medicine and biology · 2022Review
- Review
- The interplay between DNA and histone methylation: molecular mechanisms and disease implications.EMBO reports · 2021Review
- Review
- Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery.Scientific reports · 2021Article
- Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1.Nucleic acids research · 2020Article
- Molecular Structure, Binding Affinity, and Biological Activity in the Epigenome.International journal of molecular sciences · 2020Review
- Targeting non-bromodomain chromatin readers.Nature structural & molecular biology · 2019Review
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
UHRF1 is a key mediator of inheritance of epigenetic DNA methylation patterns during cell division and is a putative target for cancer therapy. Recent studies indicate that interdomain interactions critically influence UHRF1's chromatin-binding properties, including allosteric regulation of its histone binding. Here, using an integrative approach that combines small angle X-ray scattering, NMR spectroscopy, and molecular dynamics simulations, we characterized the dynamics of the tandem tudor domain-plant homeodomain (TTD-PHD) histone reader module, including its 20-residue interdomain linker. We found that the apo TTD-PHD module in solution comprises a dynamic ensemble of conformers, approximately half of which are compact conformations, with the linker lying in the TTD peptide-binding groove. These compact conformations are amenable to cooperative, high-affinity histone binding. In the remaining conformations, the linker position was in flux, and the reader adopted both extended and compact states. Using a small-molecule fragment screening approach, we identified a compound, 4-benzylpiperidine-1-carboximidamide, that binds to the TTD groove, competes with linker binding, and promotes open TTD-PHD conformations that are less efficient at H3K9me3 binding. Our work reveals a mechanism by which the dynamic TTD-PHD module can be allosterically targeted with small molecules to modulate its histone reader function for therapeutic or experimental purposes.
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