Structural basis of histone demethylation by LSD1 revealed by suicide inactivation

Nat Struct Mol Biol. 2007 Jun;14(6):535-9. doi: 10.1038/nsmb1255. Epub 2007 May 27.


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 gamma-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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Crystallization
  • Gene Silencing / physiology*
  • Histone Demethylases
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Methylation
  • Models, Molecular*
  • Molecular Sequence Data
  • Molecular Structure
  • Mutagenesis
  • Oxidoreductases, N-Demethylating / genetics*
  • Substrate Specificity


  • Histones
  • Histone Demethylases
  • KDM1A protein, human
  • Oxidoreductases, N-Demethylating

Associated data

  • PDB/2UXN