NMR Fragment-Based Screening against Tandem RNA Recognition Motifs of TDP-43
NMR Fragment-Based Screening against Tandem RNA Recognition Motifs of TDP-43
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基于 NMR 片段的 TDP-43 串联 RNA 识别基序筛选
DOI：
10.3390/ijms20133230
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发表时间：
2019
影响因子：
5.6
通讯作者：
Ruan Ke
中科院分区：
文献类型：
--
作者：
Nshogoza Gilbert;Liu Yaqian;Gao Jia;Liu Mingqing;Moududee Sayed Ala;Ma Rongsheng;Li Fudong;Zhang Jiahai;Wu Jihui;Shi Yunyu;Ruan Ke
TDP-43最初是一种核蛋白，但在病理条件下易位到细胞质中。TDP-43是一种RNA结合蛋白，由两个RNA识别基序（RRM 1和RRM 2）组成。已知RRM涉及蛋白质-核苷酸和蛋白质-蛋白质相互作用，并介导应激颗粒的形成。因此，它们协助整个TDP-43蛋白参与神经退行性疾病和癌症疾病。因此，它们是潜在的治疗靶点。蛋白质观察和配体观察的核磁共振（NMR）光谱被用来揭示小分子抑制剂对串联RRM的TDP-43。我们使用基于配体观察的NMR片段的筛选鉴定了三个弱结合串联RRM的命中。这些命中的结合拓扑结构，然后描绘的15 N-标记的串联RRM和RRM 2的化学位移扰动（CSP），分别，并通过CSP引导的高模糊驱动的生物分子对接（HADDOCK）建模。这些命中主要结合RRM 2结构域，这表明TDP-43的RRM 2结构域的可药物化性。这些命中还促进了关于针对TDP-43 RRM结构域的命中至先导物进化的进一步研究。
The TDP-43 is originally a nuclear protein but translocates to the cytoplasm in the pathological condition. TDP-43, as an RNA-binding protein, consists of two RNA Recognition Motifs (RRM1 and RRM2). RRMs are known to involve both protein-nucleotide and protein-protein interactions and mediate the formation of stress granules. Thus, they assist the entire TDP-43 protein with participating in neurodegenerative and cancer diseases. Consequently, they are potential therapeutic targets. Protein-observed and ligand-observed nuclear magnetic resonance (NMR) spectroscopy were used to uncover the small molecule inhibitors against the tandem RRM of TDP-43. We identified three hits weakly binding the tandem RRMs using the ligand-observed NMR fragment-based screening. The binding topology of these hits is then depicted by chemical shift perturbations (CSP) of the 15N-labeled tandem RRM and RRM2, respectively, and modeled by the CSP-guided High Ambiguity Driven biomolecular DOCKing (HADDOCK). These hits mainly bind to the RRM2 domain, which suggests the druggability of the RRM2 domain of TDP-43. These hits also facilitate further studies regarding the hit-to-lead evolution against the TDP-43 RRM domain.