Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, United States.
Center of Innovation in Brain Science, Tucson, Arizona 85721, United States.
ACS Chem Biol. 2020 Nov 20;15(11):2854-2859. doi: 10.1021/acschembio.0c00494. Epub 2020 Oct 12.
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. 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 . 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 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.
在这项研究中，我们针对反式激活反应（TAR）DNA 结合蛋白（TDP-43）的 N 端结构域（NTD），该结构域与几种神经退行性疾病有关。 将 50K 化合物与 TDP-43 的 NTD 结构域对接，鉴定出一种与 N 端结构域结合的小分子（nTRD22）。有趣的是，nTRD22 引起了 TDP-43 的 RNA 结合结构域（RRM）的别构调节，导致与 RNA 的结合减少。此外，用 nTRD22 孵育原代运动神经元可诱导 TDP-43 蛋白水平降低，类似于 TDP-43 RNA 结合缺陷突变体，支持 TDP-43 与 RNA 结合的破坏。最后，nTRD22 减轻了肌萎缩侧索硬化症模型中的运动障碍。我们的发现为通过 N 端结构域对 TDP-43 的 RNA 结合区域进行别构调节提供了一种令人兴奋的方法。
