Structural basis of histone demethylation by LSD1 revealed by suicide inactivation.
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.
Yang
Maojun
M
Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA.
Culhane
Jeffrey C
JC
Szewczuk
Lawrence M
LM
Gocke
Christian B
CB
Brautigam
Chad A
CA
Tomchick
Diana R
DR
Machius
Mischa
M
Cole
Philip A
PA
Yu
Hongtao
H
D000595:Amino Acid Sequence; D003460:Crystallization; D020868:Gene Silencing / Q000502:physiology*; D056466:Histone Demethylases; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016296:Mutagenesis; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D013379:Substrate Specificity
D006657:Histones; D056466:Histone Demethylases; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating