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An Allosteric Modulator of RNA Binding Targeting the N-Terminal Domain of TDP-43 Yields Neuroprotective Properties.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2020 Nov 20; Vol. 15 (11), pp. 2854-2859. Date of Electronic Publication: 2020 Oct 12. - Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Amyotrophic Lateral Sclerosis drug therapy
Amyotrophic Lateral Sclerosis metabolism
Amyotrophic Lateral Sclerosis physiopathology
Animals
Binding Sites drug effects
DNA-Binding Proteins chemistry
Disease Models, Animal
Drosophila
Humans
Molecular Docking Simulation
Small Molecule Libraries chemistry
Allosteric Regulation drug effects
DNA-Binding Proteins metabolism
Protein Domains drug effects
RNA metabolism
Small Molecule Libraries pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 15
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 33044808
- Full Text :
- https://doi.org/10.1021/acschembio.0c00494