Structural basis of LSD1-CoREST selectivity in histone H3 recognition.
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.
Forneris
Federico
F
Dipartimento di Genetica e Microbiologia, Università di Pavia, Via Ferrata 1, 27100 Pavia, Italy.
Binda
Claudia
C
Adamo
Antonio
A
Battaglioli
Elena
E
Mattevi
Andrea
A
D000818:Animals; D001665:Binding Sites; D056970:Co-Repressor Proteins; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D005415:Flavins / Q000737:chemistry / Q000378:metabolism; D056466:Histone Demethylases; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005415:Flavins; D006657:Histones; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D010455:Peptides; C485650:Rcor2 protein, mouse; D012097:Repressor Proteins; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating