Yang Maojun, Culhane Jeffrey C, Szewczuk Lawrence M, Gocke Christian B, Brautigam Chad A, Tomchick Diana R, Machius Mischa, Cole Philip A, Yu Hongtao
Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA.
Nat Struct Mol Biol. 2007 Jun;14(6):535-9. doi: 10.1038/nsmb1255. Epub 2007 May 27.
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.
组蛋白甲基化调控多种以染色质为模板的过程，包括转录。首个组蛋白赖氨酸特异性去甲基化酶（LSD1）的近期发现，改变了长期以来认为组蛋白甲基化是一种永久性表观遗传标记的观点。LSD1是一种依赖黄素腺嘌呤二核苷酸（FAD）的胺氧化酶，可使组蛋白H3赖氨酸4（H3-K4）去甲基化。然而，LSD1实现其底物特异性的机制尚不清楚。我们报道了人LSD1与炔丙胺衍生化的H3肽共价连接到FAD的晶体结构。H3采用三个连续γ转角，实现理想的侧链间距，使其N端进入一个阴离子口袋，并将甲基化的赖氨酸4定位在FAD附近以便催化。LSD1活性位点无法有效容纳甲基赖氨酸N端一侧超过三个残基，这解释了其对H3-K4的特异性。与LSD1结合的H3的异常主链构象提示了一种设计具有治疗潜力的强效LSD1抑制剂的策略。
