Synthetic trimethyllysine receptors that bind histone 3, trimethyllysine 27 (H3K27me3) and disrupt its interaction with the epigenetic reader protein CBX7

Post-translational modifications act as ‘on’ or ‘off’ switches causing downstream changes in gene transcription. Modifications such as trimethylation of lysine 27 on histone H3 (H3K27me3) cause repression of transcription and stable gene silencing, and its presence is associated with aggressive canc...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-11, Vol.21 (22), p.7004-7010
Main Authors: Tabet, Sara, Douglas, Sarah F., Daze, Kevin D., Garnett, Graham A.E., Allen, Kevin J.H., Abrioux, Emma M.M., Quon, Taylor T.H., Wulff, Jeremy E., Hof, Fraser
Format: Article
Language:English
Subjects:
Calixarenes
Calixarenes - chemical synthesis
Calixarenes - chemistry
Calixarenes - metabolism
Epigenetics
Fluorescence Polarization
Histones - chemistry
Histones - metabolism
Humans
Kinetics
Methylation
Phenols - chemical synthesis
Phenols - chemistry
Phenols - metabolism
Polycomb Repressive Complex 1 - chemistry
Polycomb Repressive Complex 1 - metabolism
Post-translational modifications
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational
Protein–protein interactions
Receptors, Artificial - chemical synthesis
Receptors, Artificial - chemistry
Receptors, Artificial - metabolism
Supramolecular chemistry
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Summary:Post-translational modifications act as ‘on’ or ‘off’ switches causing downstream changes in gene transcription. Modifications such as trimethylation of lysine 27 on histone H3 (H3K27me3) cause repression of transcription and stable gene silencing, and its presence is associated with aggressive cancers of many types. We report here macrocyclic host-type compounds that can bind H3K27me3 preferentially over unmethylated H3K27, and characterize their binding affinities and selectivities using a convenient dye-displacement method. We also show that they can disrupt the protein–protein interaction of H3K27me3 with the chromobox homolog 7 (CBX7), a methyllysine reader protein, using fluorescence polarization. These results show that sub-micromolar potencies are achievable with this family of host compounds, and suggest the possibility of their use as new tools to induce the disruption of methyllysine-mediated protein–protein interactions and to report on lysine methylation in vitro.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.09.024