Issue Date: May 28, 2007
Demethylase's Specificity Explained
The first structure of a key histone demethylation enzyme linked to a substrate-like peptide helps explain the enzyme's specificity. Histones are the main protein components of chromosomes, and the way they're methylated is a code that helps control gene transcription in cells. Histone methylation was thought to be irreversible until 2004, when the first histone demethylase, lysine-specific demethylase (LSD1), was found. But despite evidence from several LSD1 crystal structures, the way LSD1 achieves specificity for its substrate, lysine 4 in histone H3, has been a mystery. Philip A. Cole of Johns Hopkins University School of Medicine, Hongtao Yu of the University of Texas Southwestern Medical Center, in Dallas, and coworkers have now obtained a crystal structure (shown) in which LSD1 is covalently bound to a histone H3 peptide (Nat. Struct. Mol. Biol., DOI: 10.1038/nsmb1255). The structure shows that the substrate adopts several turns that fit snugly into LSD1's catalytic site, explaining the enzyme's specificity for it. The structure should aid design of LSD1 inhibitors, which might have anticancer potential.
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