Forneris Federico, Binda Claudia, Adamo Antonio, Battaglioli Elena, Mattevi Andrea
Dipartimento di Genetica e Microbiologia, Università di Pavia, Via Ferrata 1, 27100 Pavia, Italy.
J Biol Chem. 2007 Jul 13;282(28):20070-4. doi: 10.1074/jbc.C700100200. Epub 2007 May 30.
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.
组蛋白去甲基化酶LSD1通过使组蛋白H3的赖氨酸4（Lys(4)）去甲基化来调节转录。该酶与CoREST及一种底物样肽抑制剂形成复合物的晶体结构突出了一个复杂的相互作用网络以及结合肽的折叠构象。肽结构的核心由参与特定分子内氢键的精氨酸2（Arg(2)）、谷氨酰胺5（Gln(5)）和丝氨酸10（Ser(10)）形成。底物结合口袋表面的几个带电荷侧链与肽建立了静电相互作用。三维结构预测，甲基化的赖氨酸4（Lys(4)）结合在黄素辅因子前方一个溶剂不可及的位置。这种几何结构与通过黄素介导的底物氨基甲基氧化催化去甲基化反应完全一致。这些特征决定了LSD1精确的底物特异性，并提供了一个结构框架来解释其催化活性的微调以及CoREST在底物识别中的积极作用。
