Structural Basis of LSD1-CoREST Selectivity in Histone H3 Recognition

• DOI: 10.1074/jbc.c700100200
• Publication Date: 2007-05-31T00:13:54Z
• Authors: Federico Forneris; Claudia Binda; Antonio Adamo; Elena Battaglioli; Andrea Mattevi
• Keywords: 570; Nerve Tissue Proteins; histone; Crystallography, X-Ray; Substrate Specificity; Histones; Mice; 03 medical and health sciences; Multienzyme Complexes; Flavins; Animals; Enzyme Inhibitors; Protein Structure, Quaternary; Histone Demethylases; 0303 health sciences; Binding Sites; Oxidoreductases, N-Demethylating; 540; Chromatin; DNA-Binding Proteins; Repressor Proteins; Peptides; Co-Repressor Proteins; Oxidation-Reduction; epigenetic; Protein Binding

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 Arg(2), Gln(5), 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 Lys(4) 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.