ArticleJournal of medicinal chemistry2022
Systematic Variation of Both the Aromatic Cage and Dialkyllysine via GCE-SAR Reveal Mechanistic Insights in CBX5 Reader Protein Binding.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
- Influence of the Electrostatic Tuning of Alkyl and Benzyl Groups on Cation-π Interactions in Histone Reader Proteins and β-Hairpin Peptides.Biochemistry · 2026Article
- Epigenetic reader chromodomain as a potential therapeutic target.RSC chemical biology · 2025Review
- 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
- WDR5 Binding to Histone Serotonylation Is Driven by an Edge-Face Aromatic Interaction with Unexpected Electrostatic Effects.Journal of the American Chemical Society · 2024Article
- Contribution of Electrostatic CHJournal 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
- Engineered Biocatalytic Synthesis of β-N-Substituted-α-Amino Acids.Angewandte Chemie (International ed. in English) · 2023Article
- Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function.Chemical science · 2023Article
- Chemical tools targeting readers of lysine methylation.Current opinion in chemical biology · 2023Review
- Evaluation of acyllysine isostere interactions with the aromatic pocket of the AF9 YEATS domain.Protein science : a publication of the Protein Society · 2023Article
- Virtual Special Issue: Epigenetics 2022.ACS pharmacology & translational science · 2022Article
- Virtual Special Issue: Epigenetics 2022.ACS medicinal chemistry letters · 2022Article
- Covalent labeling of a chromatin reader domain using proximity-reactive cyclic peptides.Chemical science · 2022Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Development of inhibitors for histone methyllysine reader proteins is an active area of research due to the importance of reader protein-methyllysine interactions in transcriptional regulation and disease. Optimized peptide-based chemical probes targeting methyllysine readers favor larger alkyllysine residues in place of methyllysine. However, the mechanism by which these larger substituents drive tighter binding is not well understood. This study describes the development of a two-pronged approach combining genetic code expansion (GCE) and structure-activity relationships (SAR) through systematic variation of both the aromatic binding pocket in the protein and the alkyllysine residues in the peptide to probe inhibitor recognition in the CBX5 chromodomain. We demonstrate a novel change in driving force for larger alkyllysines, which weaken cation-π interactions but increases dispersion forces, resulting in tighter binding. This GCE-SAR approach establishes discrete energetic contributions to binding from both ligand and protein, providing a powerful tool to gain mechanistic understanding of SAR trends.
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Registered trials
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