Structural basis of histone demethylation by LSD1 revealed by suicide inactivation

Maojun Yang, Jeffrey C. Culhane, Lawrence M. Szewczuk, Christian B. Gocke, Chad A. Brautigam, Diana R. Tomchick, Mischa MacHius, Philip A. Cole, Hongtao Yu

Research output: Contribution to journalArticlepeer-review

141 Scopus citations


Histone methylation regulates diverse chromatin-templated processes, including transcription. The recent discovery of the first histone lysine-specific demethylase (LSD1) has changed the long-held view that histone methylation is a permanent epigenetic mark. LSD1 is a flavin adenine dinucleotide (FAD)-dependent amine oxidase that demethylates histone H3 Lys4 (H3-K4). However, the mechanism by which LSD1 achieves its substrate specificity is unclear. We report the crystal structure of human LSD1 with a propargylamine-derivatized H3 peptide covalently tethered to FAD. H3 adopts three consecutive γ-turns, enabling an ideal side chain spacing that places its N terminus into an anionic pocket and positions methyl-Lys4 near FAD for catalysis. The LSD1 active site cannot productively accommodate more than three residues on the N-terminal side of the methyllysine, explaining its H3-K4 specificity. The unusual backbone conformation of LSD1-bound H3 suggests a strategy for designing potent LSD1 inhibitors with therapeutic potential.

Original languageEnglish (US)
Pages (from-to)535-539
Number of pages5
JournalNature Structural and Molecular Biology
Issue number6
StatePublished - Jun 2007
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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