Belle Roman, Kamps Jos J A G, Poater Jordi, Kumar Kiran, Pieters Bas J G E, Salah Eidarus, Claridge Timothy D W, Paton Robert S, Matthias Bickelhaupt F, Kawamura Akane, Schofield Christopher J, Mecinović Jasmin
Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
Chemistry-School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
Commun Chem. 2022 Mar 7;5(1). doi: 10.1038/s42004-022-00640-4. eCollection 2022 Dec.
-Methylation of lysine residues in histones plays an essential role in the regulation of eukaryotic transcription. The 'highest' methylation mark, -trimethyllysine, is specifically recognised by -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 -trimethyllysine analogue, i.e. its trimethylphosphonium derivative (Kme), by -trimethyllysine histone binding proteins and trimethyllysine demethylases. Calorimetric and computational studies with histone binding proteins reveal that H3K4me binds more tightly than the natural H3K4me 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, . 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.
组蛋白中赖氨酸残基的甲基化在真核转录调控中起关键作用。“最高级”的甲基化标记，即三甲基赖氨酸，由三甲基赖氨酸结合“读取器”结构域特异性识别，并在依赖于2-氧代戊二酸的JmjC加氧酶催化下发生去甲基化。我们报告了关于三甲基赖氨酸组蛋白结合蛋白和三甲基赖氨酸去甲基化酶对最接近的带正电荷的三甲基赖氨酸类似物，即其三甲基鏻衍生物（Kme）的识别研究。对组蛋白结合蛋白的量热和计算研究表明，H3K4me比天然H3K4me底物结合更紧密，尽管结合亲和力的相对差异各不相同。对JmjC去甲基化酶的研究表明，其中一些（但不是全部）可以接受其天然底物的鏻类似物，并且通过用磷取代氮可以改变甲基化状态选择性。综合结果表明，非常细微的变化，即用磷取代氮，会显著影响配体与读取器结构域/去甲基化酶之间的相互作用，我们希望这些知识能激发开发调节其活性的高选择性小分子。
