2UXN

Structural Basis of Histone Demethylation by LSD1 Revealed by Suicide Inactivation

Summary for 2UXN

• Entry DOI: 10.2210/pdb2uxn/pdb
• Related: 2B2T 2B2U 2B2V 2B2W 2C1J 2C1N 2COM 2CV5 2H94 2IW5 2UXX
• Descriptor: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1, REST COREPRESSOR 1, HISTONE H3.1, ... (7 entities in total)
• Functional Keywords: oxidoreductase-transcription regulator complex, oxidoreductase-repressor complex, histone demethylase, fad, lsd1, corest, repressor, transcription regulation, host-virus interaction, chromatin demethylation, nuclear protein, phosphorylation, chromatin regulator, nucleosomes, transcription, oxidoreductase, oxidoreductase/transcription regulator
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus: O60341 Q9UKL0 P68431
• Total number of polymer chains: 3
• Total formula weight: 103819.83

Authors

Yang, M.,Culhane, J.C.,Szewczuk, L.M.,Gocke, C.B.,Brautigam, C.A.,Tomchick, D.R.,Machius, M.,Cole, P.A.,Yu, H. (deposition date: 2007-03-28, release date: 2007-05-29, Last modification date: 2025-04-09)

Primary citation

Yang, M.,Culhane, J.C.,Szewczuk, L.M.,Gocke, C.B.,Brautigam, C.A.,Tomchick, D.R.,Machius, M.,Cole, P.A.,Yu, H.
Structural Basis of Histone Demethylation by Lsd1 Revealed by Suicide Inactivation.
Nat.Struct.Mol.Biol., 14:535-, 2007

PubMed Abstract: 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.

PubMed: 17529991
DOI: 10.1038/NSMB1255

Experimental method

X-RAY DIFFRACTION (2.72 Å)