AI Article Synopsis
- This study presents a novel method to develop the first inhibitors for CBX7, a protein that recognizes methylated histones and is linked to tumor suppression.
- Researchers designed small peptides that mimic trimethyllysine to disrupt the CBX7-H3K27me3 complex, and determined their effectiveness using techniques like fluorescence polarization and isothermal titration calorimetry.
- One identified inhibitor showed strong binding (∼200 nM potency) and significant selectivity against similar proteins, marking a significant advance in chromodomain research.
Article Abstract
We report here a peptide-driven approach to create first inhibitors of the chromobox homolog 7 (CBX7), a methyllysine reader protein. CBX7 uses its chromodomain to bind histone 3, lysine 27 trimethylated (H3K27me3), and this recognition event is implicated in silencing multiple tumor suppressors. Small trimethyllysine containing peptides were used as the basic scaffold from which potent ligands for disruption of CBX7-H3K27me3 complex were developed. Potency of ligands was determined by fluorescence polarization and/or isothermal titration calorimetry. Binding of one ligand was characterized in detail using 2D NMR and X-ray crystallography, revealing a structural motif unique among human CBX proteins. Inhibitors with a ∼200 nM potency for CBX7 binding and 10-fold/400-fold selectivity over related CBX8/CBX1 proteins were identified. These are the first reported inhibitors of any chromodomain.
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| http://dx.doi.org/10.1021/jm401487x | DOI Listing |
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