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. 2006 Jul;13(7):626-32.
doi: 10.1038/nsmb1113. Epub 2006 Jun 25.

Crystal structure and mechanism of human lysine-specific demethylase-1

Pete Stavropoulos  1 , Günter Blobel, André Hoelz
Affiliations

Crystal structure and mechanism of human lysine-specific demethylase-1

Pete Stavropoulos et al. Nat Struct Mol Biol. 2006 Jul.

Abstract

The reversible methylation of specific lysine residues in histone tails is crucial in epigenetic gene regulation. LSD1, the first known lysine-specific demethylase, selectively removes monomethyl and dimethyl, but not trimethyl modifications of Lys4 or Lys9 of histone-3. Here, we present the crystal structure of LSD1 at 2.9-A resolution. LSD1 forms a highly asymmetric, closely packed domain structure from which a long helical 'tower' domain protrudes. The active site cavity is spacious enough to accommodate several residues of the histone tail substrate, but does not appear capable of recognizing the different methylation states of the substrate lysine. This supports the hypothesis that trimethylated lysine is chemically rather than sterically discriminated. We present a biochemical analysis of LSD1 mutants that identifies crucial residues in the active site cavity and shows the importance of the SWIRM and tower domains for catalysis.

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