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An Allosteric Modulator of RNA Binding Targeting the N-Terminal Domain of TDP-43 Yields Neuroprotective Properties
ACS Chemical Biology ( IF 4 ) Pub Date : 2020-10-12 , DOI: 10.1021/acschembio.0c00494
Niloufar Mollasalehi 1, 2, 3 , Liberty Francois-Moutal 1, 2 , David D Scott 1, 2 , Judith A Tello 1, 2 , Haley Williams 1, 2 , Brendan Mahoney 4 , Jacob M Carlson 1, 2 , Yue Dong 5, 6 , Xingli Li 7 , Victor G Miranda 1, 2 , Vijay Gokhale 8 , Wei Wang 5, 6 , Sami J Barmada 7 , May Khanna 1, 2
Affiliation  

In this study, we targeted the N-terminal domain (NTD) of transactive response (TAR) DNA binding protein (TDP-43), which is implicated in several neurodegenerative diseases. In silico docking of 50K compounds to the NTD domain of TDP-43 identified a small molecule (nTRD22) that is bound to the N-terminal domain. Interestingly, nTRD22 caused allosteric modulation of the RNA binding domain (RRM) of TDP-43, resulting in decreased binding to RNA in vitro. Moreover, incubation of primary motor neurons with nTRD22 induced a reduction of TDP-43 protein levels, similar to TDP-43 RNA binding-deficient mutants and supporting a disruption of TDP-43 binding to RNA. Finally, nTRD22 mitigated motor impairment in a Drosophila model of amyotrophic lateral sclerosis. Our findings provide an exciting way of allosteric modulation of the RNA-binding region of TDP-43 through the N-terminal domain.

中文翻译:

靶向 TDP-43 N 末端结构域的 RNA 结合变构调节剂产生神经保护特性

在这项研究中,我们针对与几种神经退行性疾病有关的交互反应 (TAR) DNA 结合蛋白 (TDP-43) 的 N 端结构域 (NTD)。50K 化合物与 TDP-43 的 NTD 域的计算机对接鉴定了一个与 N 端域结合的小分子 (nTRD22)。有趣的是,nTRD22 引起 TDP-43 的 RNA 结合域 (RRM) 的变构调节,导致体外与 RNA 的结合降低。此外,初级运动神经元与 nTRD22 的孵育诱导了 TDP-43 蛋白水平的降低,类似于 TDP-43 RNA 结合缺陷突变体,并支持 TDP-43 与 RNA 结合的破坏。最后,nTRD22 减轻了果蝇的运动障碍肌萎缩侧索硬化模型。我们的发现提供了一种通过 N 端结构域对 TDP-43 的 RNA 结合区进行变构调节的令人兴奋的方式。
更新日期:2020-11-21
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