Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 400, Issue 1, Pages 1-7Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2010.04.048
Keywords
epigenetics; histone lysine methylation; enzymatic inhibition; lysine mimics
Categories
Funding
- Biochemistry Department of Emory University School of Medicine
- National Institutes of Health [R01GM068680, R56DK082678, U54HG003918]
- Welch Foundation [G-1495]
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Dynamic histone lysine methylation involves the activities of modifying enzymes (writers), enzymes removing modifications (erasers), and readers of the histone code. One common feature of these activities is the recognition of lysines in methylated and unmethylated states, whether they are substrates, reaction products, or binding partners. We applied the concept of adding a lysine mimic to an established inhibitor (BIX-01294) of histone H3 lysine 9 methyltransferases G9a and G9a-like protein by including a 5-aminopentyloxy moiety, which is inserted into the target lysine-binding channel and becomes methylated by G9a-like protein, albeit slowly. The compound enhances its potency in vitro and reduces cell toxicity in vivo. We suggest that adding a lysine or methyl-lysine mimic should be considered in the design of small-molecule inhibitors for other methyllysine writers, erasers, and readers. (C) 2010 Elsevier Ltd. All rights reserved.
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