Structural basis of LSD1-CoREST selectivity in histone H3 recognition

Federico Forneris, Claudia Binda, Antonio Adamo, Elena Battaglioli, Andrea Mattevi

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Histone demethylase LSD1 regulates transcription by demethylating Lys 4 of histone H3. The crystal structure of the enzyme in complex with CoREST and a substrate-like peptide inhibitor highlights an intricate network of interactions and a folded conformation of the bound peptide. The core of the peptide structure is formed by Arg2, Gln5, and Ser 10, which are engaged in specific intramolecular H-bonds. Several charged side chains on the surface of the substrate-binding pocket establish electrostatic interactions with the peptide. The three-dimensional structure predicts that methylated Lys4 binds in a solvent inaccessible position in front of the flavin cofactor. This geometry is fully consistent with the demethylation reaction being catalyzed through a flavin-mediated oxidation of the substrate amino-methyl group. These features dictate the exquisite substrate specificity of LSD1 and provide a structural framework to explain the fine tuning of its catalytic activity and the active role of CoREST in substrate recognition.

Original languageEnglish
Pages (from-to)20070-20074
Number of pages5
JournalJournal of Biological Chemistry
Issue number28
Publication statusPublished - Jul 13 2007


ASJC Scopus subject areas

  • Biochemistry

Cite this

Forneris, F., Binda, C., Adamo, A., Battaglioli, E., & Mattevi, A. (2007). Structural basis of LSD1-CoREST selectivity in histone H3 recognition. Journal of Biological Chemistry, 282(28), 20070-20074.