Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins.
Reading and erasing of the phosphonium analogue of trimethyllysine by epigenetic proteins.
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DOI：
10.1038/s42004-022-00640-4
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发表时间：
2022-12
影响因子：
5.9
通讯作者：
Mecinović J
中科院分区：
文献类型：
--
作者：
Belle R;Kamps JJAG;Poater J;Kumar K;Pieters BJGE;Salah E;Claridge TDW;Paton RS;Matthias Bickelhaupt F;Kawamura A;Schofield CJ;Mecinović J
组蛋白中赖氨酸残基的Nε甲基化在真核转录调控中起着重要作用。最高的甲基化标记Nε-三甲基赖氨酸由Nε-三甲基赖氨酸结合的‘阅读器’结构域特异性识别，并在依赖2-氧戊二酸的JmjC加氧酶的催化下经历去甲基化。本文报道了N-ε-三甲基赖氨酸组蛋白结合蛋白和N-ε-三甲基赖氨酸去甲基酶对最接近正电的N-ε-三甲基赖氨酸类似物--三甲基膦衍生物(KPme3)的识别作用。组蛋白结合蛋白的量热和计算研究表明，H3KP4me3比天然H3K4me3底物结合得更紧密，尽管结合亲和力的相对差异有所不同。对JmjC去甲基酶的研究表明，它们中的一些，但不是所有的，都可以接受其天然底物中的膦类似物，并且可以通过用氮取代磷来改变甲基化状态的选择性。综合结果显示，非常细微的变化，例如用氮取代磷，可以显著影响配体和阅读器结构域/去甲基酶之间的相互作用，我们希望这些知识将激励高选择性小分子的发展，调节其活性。组蛋白中赖氨酸残基的Nε甲基化在真核转录调控中起着至关重要的作用，了解组蛋白Nε甲基赖氨酸读取器和擦除器在多大程度上表现出选择性具有基础和医学意义。在这里，作者研究了Nε-三甲基赖氨酸的膦类似物，发现从氮到磷的微妙取代大大影响了它与Nε-甲基赖氨酸读取器和擦除器的相互作用。
Nε-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The ‘highest’ methylation mark, Nε-trimethyllysine, is specifically recognised by Nε-trimethyllysine binding ‘reader’ domains, and undergoes demethylation, as catalysed by 2-oxoglutarate dependent JmjC oxygenases. We report studies on the recognition of the closest positively charged Nε-trimethyllysine analogue, i.e. its trimethylphosphonium derivative (KPme3), by Nε-trimethyllysine histone binding proteins and Nε-trimethyllysine demethylases. Calorimetric and computational studies with histone binding proteins reveal that H3KP4me3 binds more tightly than the natural H3K4me3 substrate, though the relative differences in binding affinity vary. Studies with JmjC demethylases show that some, but not all, of them can accept the phosphonium analogue of their natural substrates and that the methylation state selectivity can be changed by substitution of nitrogen for phosphorus. The combined results reveal that very subtle changes, e.g. substitution of nitrogen for phosphorus, can substantially affect interactions between ligand and reader domains / demethylases, knowledge that we hope will inspire the development of highly selective small molecules modulating their activity. Nε-methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription, and understanding the extent to which histone Nε-methyllysine readers and erasers can manifest selectivity is of fundamental and medicinal interest. Here, the authors study the phosphonium analogue of Nε-trimethyllysine, finding that a subtle substitution from nitrogen to phosphorus substantially affects its interactions with Nε-methyllysine readers and erasers.
影响因子：
16.6
作者：
Hopkinson, Richard J.;Walport, Louise J.;Muenzel, Martin;Rose, Nathan R.;Smart, Tristan J.;Kawamura, Akane;Claridge, Timothy D. W.;Schofield, Christopher J.
通讯作者：
Schofield, Christopher J.