Structural basis of histone demethylation by LSD1 revealed by suicide inactivation
Structural basis of histone demethylation by LSD1 revealed by suicide inactivation
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DOI：
10.1038/nsmb1255
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发表时间：
2007-06-01
影响因子：
16.8
通讯作者：
Yu, Hongtao
中科院分区：
文献类型：
--
作者：
Yang, Maojun;Culhane, Jeffrey C.;Yu, Hongtao
组蛋白甲基化调节不同的染色质模板化过程，包括转录。最近发现的第一个组蛋白赖氨酸特异性脱甲基酶（LSD 1）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。LSD 1是黄素腺嘌呤二核苷酸（FAD）依赖性胺氧化酶，其使组蛋白H3 Lys 4（H3-K4）去甲基化。然而，LSD 1实现其底物特异性的机制尚不清楚。我们报告的晶体结构与炔丙胺衍生的H3肽共价拴到FAD的人LSD 1。H3采用三个连续的c-转角，实现了理想的侧链间距，将其N末端置于阴离子口袋中，并将甲基-Lys 4定位在FAD附近用于催化。LSD 1活性位点不能有效地容纳甲基赖氨酸N-末端侧的三个以上残基，这解释了其H3-K4特异性。LSD 1结合H3的不寻常骨架构象表明了设计具有治疗潜力的有效LSD 1抑制剂的策略。
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 c-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.