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首页> 外文期刊>Nature >Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity
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Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity

机译：组蛋白脱甲基酶JMJD2A的晶体结构揭示了底物特异性的基础

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Post-translational histone modification has a fundamental role in chromatin biology and is proposed to constitute a 'histone code' in epigenetic regulation. Differential methylation of histone H3 and H4 lysyl residues regulates processes including heterochro-matin formation, X-chromosome inactivation, genome imprinting, DNA repair and transcriptional regulation. The discovery of lysyl demethylases using flavin (amine oxidases) or Fe(Ⅱ) and 2-oxoglutarate as cofactors (2OG oxygenases) has changed the view of methylation as a stable epigenetic marker. However, little is known about how the demethylases are selective for particular lysyl-containing sequences in specific methylation states, a key to understanding their functions. Here we reveal how human JMJD2A (jumonji domain containing 2A), which is selective towards tri- and dimethylated histone H3 lysyl residues 9 and 36 (H3K9me3/me2 and H3K36me3/me2), discriminates between methylation states and achieves sequence selectivity for H3K9. We report structures of JMJD2A-Ni(Ⅱ)-Zn(Ⅱ) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36. The structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site. We propose a mechanism for achieving methylation state selectivity involving the orientation of the substrate methyl groups towards a ferryl intermediate. The results suggest distinct recognition mechanisms in different demethylase subfamilies and provide a starting point to develop chemical tools for drug discovery and to study and dissect the complexity of reversible histone methylation and its role in chromatin biology.
机译：翻译后的组蛋白修饰在染色质生物学中具有基本作用，并被提议在表观遗传调控中构成“组蛋白密码”。组蛋白H3和H4赖氨酰残基的差异甲基化可调节过程，包括异色生瘤素形成，X染色体失活，基因组印迹，DNA修复和转录调控。使用黄素（胺氧化酶）或Fe（Ⅱ）和2-氧戊二酸作为辅因子（2OG加氧酶）的赖氨酰脱甲基酶的发现改变了甲基化作为稳定表观遗传标记的观点。然而，对于脱甲基酶如何对处于特定甲基化状态的特定含赖氨酰序列的选择性了解甚少，这是理解其功能的关键。在这里我们揭示了对三和二甲基化组蛋白H3赖氨酸残基9和36（H3K9me3 / me2和H3K36me3 / me2）有选择性的人JMJD2A（含有2A的jumonji域）如何区分甲基化状态并实现对H3K9的序列选择性。我们报告了JMJD2A-Ni（Ⅱ）-Zn（Ⅱ）抑制剂复合物的结构，该复合物结合了H3K9的三，二和单甲基形式以及H3K36的三甲基形式。该结构揭示了赖氨酰结合口袋，其中底物以涉及Zn结合位点的不同弯曲构象结合。我们提出了一种用于实现甲基化状态选择性的机制，该机制涉及底物甲基朝向小轮中间体的取向。结果表明在不同的脱甲基酶亚家族中不同的识别机制，并为开发用于药物发现的化学工具以及研究和剖析可逆组蛋白甲基化的复杂性及其在染色质生物学中的作用提供了起点。

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