title: Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases.
abstract: Until 2004, many researchers believed that protein methylation in eukaryotic cells was an irreversible reaction. However, the discovery of lysine-specific demethylase 1 in 2004 drastically changed this view and the concept of chromatin regulation. Since then, the enzymes responsible for lysine demethylation and their cellular substrates, biological significance, and selective regulation have become major research topics in epigenetics and chromatin biology. Many cell-permeable inhibitors for lysine demethylases have been developed, including both target-specific and nonspecific inhibitors. Structural understanding of how these inhibitors bind to lysine demethylases is crucial both for validation of the inhibitors as chemical probes and for the rational design of more potent, target-specific inhibitors. This review focuses on published small-molecule inhibitors targeted at the two flavin adenine dinucleotide-dependent lysine demethylases, lysine-specific demethylases 1 and 2, and how the inhibitors interact with the tertiary structures of the enzymes.
authors.affiliation: a Epigenetics Drug Discovery Unit , RIKEN Center for Life Science Technologies , Suehiro-cho, Tsurumi, Yokohama , Kanagawa , Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Niwa
authors.affiliation: a Epigenetics Drug Discovery Unit , RIKEN Center for Life Science Technologies , Suehiro-cho, Tsurumi, Yokohama , Kanagawa , Japan.|b PRESTO, Japan Science and Technology Agency (JST) , Honcho, Kawaguchi , Saitama , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Umehara
mesh_terms: D002843:Chromatin / Q000737:chemistry / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D005182:Flavin-Adenine Dinucleotide / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D002843:Chromatin; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D005182:Flavin-Adenine Dinucleotide; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: Chromatin; FAD; LSD1; LSD2; crystal structure; epigenetics; histone; nucleosome; transcription