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Methods Enzymol. 2012;512:161-85. doi: 10.1016/B978-0-12-391940-3.00008-1.

High-throughput strategy to identify inhibitors of histone-binding domains.

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Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.


Many epigenetic proteins recognize the posttranslational modification state of chromatin through their histone-binding domains and thereby recruit nuclear complexes to specific loci within the genome. A number of these domains have been implicated in cancer and other diseases through aberrant binding of chromatin; therefore, identifying small molecules that disrupt histone binding could be a powerful mechanism for disease therapy. We have developed a high-throughput assay for the detection of histone peptide-domain interactions utilizing AlphaScreen technology. Here, we describe how the assay can be first optimized and then performed for high-throughput screening of small molecule-binding inhibitors. We also describe strategies for biochemical validation of small molecules identified.

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