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Issue 9, 2012
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Supramolecular hosts that recognize methyllysines and disrupt the interaction between a modified histone tail and its epigenetic reader protein

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Abstract

Post-translational modifications of proteins (including phosphorylation, acetylation and methylation, among others) frequently carry out their biological functions by serving as ‘on’ switches for proteinprotein interactions. As highly localized and perfectly defined hot-spots for proteinprotein binding, they are a diverse set of motifs that collectively offer great promise as targets for therapeutic intervention and fundamental studies of chemical biology. Recent years have seen the discovery of a very large number of such modification sites on the unstructured tails of proteins, including histones and the tumor suppressor p53. These unstructured protein elements do not present concave binding pockets, and as such cannot be targeted by the conventional small-molecule agents of chemical biology and medicinal chemistry. We report here a family of calixarene-based supramolecular hosts that bind selectively and with high affinity to histone trimethyllysine motifs that are relevant to gene regulation and oncogenesis. We show that these compounds constitute a novel class of proteinprotein interaction disruptors and that they can operate selectively against their targeted trimethyllysine sites even in highly complex protein substrates bearing a background of many unmethylated lysines and arginines.

Graphical abstract: Supramolecular hosts that recognize methyllysines and disrupt the interaction between a modified histone tail and its epigenetic reader protein

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Article information


Submitted
10 May 2012
Accepted
21 Jun 2012
First published
21 Jun 2012

Chem. Sci., 2012,3, 2695-2699
Article type
Edge Article

Supramolecular hosts that recognize methyllysines and disrupt the interaction between a modified histone tail and its epigenetic reader protein

K. D. Daze, T. Pinter, C. S. Beshara, A. Ibraheem, S. A. Minaker, M. C. F. Ma, R. J. M. Courtemanche, R. E. Campbell and F. Hof, Chem. Sci., 2012, 3, 2695
DOI: 10.1039/C2SC20583A

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