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A proteome-wide atlas of lysine-reactive chemistry
Nature Chemistry ( IF 19.2 ) Pub Date : 2021-09-09 , DOI: 10.1038/s41557-021-00765-4
Mikail E Abbasov 1, 2 , Madeline E Kavanagh 1 , Taka-Aki Ichu 1 , Michael R Lazear 1 , Yongfeng Tao 1 , Vincent M Crowley 1 , Christopher W Am Ende 3 , Stephan M Hacker 4 , Jordan Ho 5 , Melissa M Dix 1 , Radu Suciu 1 , Matthew M Hayward 3 , Laura L Kiessling 5 , Benjamin F Cravatt 1
Affiliation  

Recent advances in chemical proteomics have begun to characterize the reactivity and ligandability of lysines on a global scale. Yet, only a limited diversity of aminophilic electrophiles have been evaluated for interactions with the lysine proteome. Here, we report an in-depth profiling of >30 uncharted aminophilic chemotypes that greatly expands the content of ligandable lysines in human proteins. Aminophilic electrophiles showed disparate proteomic reactivities that range from selective interactions with a handful of lysines to, for a set of dicarboxaldehyde fragments, remarkably broad engagement of the covalent small-molecule–lysine interactions captured by the entire library. We used these latter ‘scout’ electrophiles to efficiently map ligandable lysines in primary human immune cells under stimulatory conditions. Finally, we show that aminophilic compounds perturb diverse biochemical functions through site-selective modification of lysines in proteins, including protein–RNA interactions implicated in innate immune responses. These findings support the broad potential of covalent chemistry for targeting functional lysines in the human proteome.



中文翻译:

蛋白质组范围的赖氨酸反应化学图谱

化学蛋白质组学的最新进展已经开始在全球范围内表征赖氨酸的反应性和配体能力。然而,仅评估了有限多样性的亲氨亲电子试剂与赖氨酸蛋白质组的相互作用。在这里,我们报告了超过 30 种未知的亲氨化学型的深入分析,这极大地扩展了人类蛋白质中可配体赖氨酸的含量。氨基亲电子试剂显示出不同的蛋白质组学反应性,从与少数赖氨酸的选择性相互作用到对于一组二甲醛片段,整个文库捕获的共价小分子-赖氨酸相互作用的广泛参与。我们使用这些后一种“侦察”亲电体在刺激条件下有效地绘制原代人类免疫细胞中的可配体赖氨酸。最后,我们表明,亲氨化合物通过对蛋白质中赖氨酸的位点选择性修饰,包括与先天免疫反应有关的蛋白质-RNA相互作用,扰乱了多种生化功能。这些发现支持了共价化学在人类蛋白质组中靶向功能性赖氨酸的广泛潜力。

更新日期:2021-09-09
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