ArticleChemical science2022
Covalent labeling of a chromatin reader domain using proximity-reactive cyclic peptides.
Article in Chemical science, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Application of a MALDI mass spectrometry assay to identify covalent fragments targeting the methyl-lysine reader protein MPP8.SLAS discovery : advancing life sciences R & D · 2026Article
- Preferential formation of NUP98-KDM5A condensates at specific H3K4me3-rich loci drives leukemogenic gene expression.bioRxiv : the preprint server for biology · 2026Article
- Stapled histone H3 tails are super-substrates for lysine methyltransferase SETD7.Chemical science · 2026Article
- An Intrinsically Disordered Region of Histone Demethylase KDM5A Activates Catalysis Through Interactions With the Nucleosomal Acidic Patch and DNA.Journal of molecular biology · 2025Article
- Intrastrand Peptide Staples That Promote β-Sheet Folding, Self-Assembly, and Amyloid Seeding.Journal of the American Chemical Society · 2025Article
- HTS Identifies NUP98-KDM5A-PHD3 Domain Ligands with Novel Scaffolds.ACS medicinal chemistry letters · 2025Article
- Advances in sulfonyl exchange chemical biology: expanding druggable target space.Chemical science · 2025Review
- An intrinsically disordered region of histone demethylase KDM5A activates catalysis through interactions with the nucleosomal acidic patch and DNA.bioRxiv : the preprint server for biology · 2025Article
- SuFEx Chemistry Enables Covalent Assembly of a 280-kDa 18-Subunit Pore-Forming Complex.Journal of the American Chemical Society · 2024Article
- Trimethyllysine Reader Proteins Exhibit Widespread Charge-Agnostic Binding via Different Mechanisms to Cationic and Neutral Ligands.Journal of the American Chemical Society · 2024Article
- Recent developments in catalysis and inhibition of the Jumonji histone demethylases.Current opinion in structural biology · 2023Review
- Review
- Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function.Chemical science · 2023Article
- Recent advances in the development of therapeutic peptides.Trends in pharmacological sciences · 2023Review
- Non-histone binding functions of PHD fingers.Trends in biochemical sciences · 2023Review
- Chemical tools targeting readers of lysine methylation.Current opinion in chemical biology · 2023Review
- Stretching Peptides to Generate Small Molecule β-Strand Mimics.ACS central science · 2023Article
- Solid Phase Synthesis of Fluorosulfate Containing Macrocycles for Chemoproteomic Workflows.bioRxiv : the preprint server for biology · 2023Article
- Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex.Journal of the American Chemical Society · 2022Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Chemical probes for chromatin reader proteins are valuable tools for investigating epigenetic regulatory mechanisms and evaluating whether the target of interest holds therapeutic potential. Developing potent inhibitors for the plant homeodomain (PHD) family of methylation readers remains a difficult task due to the charged, shallow and extended nature of the histone binding site that precludes effective engagement of conventional small molecules. Herein, we describe the development of novel proximity-reactive cyclopeptide inhibitors for PHD3-a trimethyllysine reader domain of histone demethylase KDM5A. Guided by the PHD3-histone co-crystal structure, we designed a sidechain-to-sidechain linking strategy to improve peptide proteolytic stability whilst maintaining binding affinity. We have developed an operationally simple solid-phase macrocyclization pathway, capitalizing on the inherent reactivity of the dimethyllysine ε-amino group to generate scaffolds bearing charged tetraalkylammonium functionalities that effectively engage the shallow aromatic 'groove' of PHD3. Leveraging a surface-exposed lysine residue on PHD3 adjacent to the ligand binding site, cyclic peptides were rendered covalent through installation of an arylsulfonyl fluoride warhead. The resulting lysine-reactive cyclic peptides demonstrated rapid and efficient labeling of the PHD3 domain in HEK293T lysates, showcasing the feasibility of employing proximity-induced reactivity for covalent labeling of this challenging family of reader domains.
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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.