NMR Fragment-Based Screening against Tandem RNA Recognition Motifs of TDP-43

• Published in: International journal of molecular sciences 2019-06, Vol.20 (13), p.3230
• Main Authors: Nshogoza, Gilbert, Liu, Yaqian, Gao, Jia, Liu, Mingqing, Moududee, Sayed Ala, Ma, Rongsheng, Li, Fudong, Zhang, Jiahai, Wu, Jihui, Shi, Yunyu, Ruan, Ke
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Apoptosis; Binding Sites; Biosynthesis; Breast cancer; Cell cycle; Cell division; Cell growth; Cervical cancer; Cervix; Cytoplasm; Decay rate; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; epigenetics; Experiments; Gene expression; High-throughput screening; Humans; Kinases; Ligands; Localization; Magnetic Resonance Spectroscopy; Metabolism; Metastasis; MicroRNAs; Molecular Docking Simulation; NMR fragment-based screening; Protein Binding; protein-RNA interaction; Proteins; RRM domain inhibitor; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Spectrum analysis; TDP-43
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20133230

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 N-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.