A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.
A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.
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DOI：
10.1038/nature11262
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发表时间：
2012-08-16
期刊：
影响因子：
64.8
通讯作者：
Wilson DM
中科院分区：
文献类型：
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作者：
Kruidenier L;Chung CW;Cheng Z;Liddle J;Che K;Joberty G;Bantscheff M;Bountra C;Bridges A;Diallo H;Eberhard D;Hutchinson S;Jones E;Katso R;Leveridge M;Mander PK;Mosley J;Ramirez-Molina C;Rowland P;Schofield CJ;Sheppard RJ;Smith JE;Swales C;Tanner R;Thomas P;Tumber A;Drewes G;Oppermann U;Patel DJ;Lee K;Wilson DM
组蛋白去甲基酶家族是依赖于Fe2+和α的酮戊二酸加氧酶，是转录调控染色质复合体的重要组成部分。这些酶在甲基化状态和序列特定的情况下使组蛋白中的赖氨酸残基去甲基化。为了从机制上理解组蛋白赖氨酸去甲基酶在真核转录、基因组完整性和表观遗传以及发育、生理和疾病中的作用，人们付出了大量的努力。然而，由于缺乏任何选择性的抑制剂，JMJ酶的去甲基酶活性在调节细胞反应中的相关性仍然知之甚少。在这里，我们提出了一种结构导向的小分子和化学蛋白质组学方法来阐明H3K27me3特异性去甲基酶亚家族(KDM6亚家族成员JMJD3和UTX)的功能作用。人和小鼠JMJD3的连接结构为KDM6亚家族去甲基酶识别辅因子、底物和抑制剂的特异性决定因素提供了新的见解。我们利用这些结构特征产生了第一个对H3K27me3特异性JMJ亚家族具有选择性的小分子催化位点抑制剂。我们证明，这种抑制物以一种新的方式结合，并减少内毒素诱导的人原代巨噬细胞促炎细胞因子的产生，这一过程依赖于JMJD3和UTX。我们的结果解决了与H3K27特异性JMJ在调节疾病相关炎症反应中的催化功能相关的模棱两可的问题，并为设计小分子抑制剂以允许跨JMJ家族进行选择性药物干预提供了鼓励。
The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family.