TARDBP

TAR DNA-binding protein 43

Score: 0.510 Price: $0.51 Low Druggability Status: active Wiki: TARDBP

🟡 ALS / Motor Neuron Disease 🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

575

DEBATES

3D Protein Structure

🧬 TARDBP — PDB 2N3X Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.43

Clinical Stage

Phase III

Target Class

Transcription Factor

Safety

0.20

Druggability Analysis

Drug Development0.45

Structural Tractability0.85

Target Class0.50

Safety Profile0.20

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (1 compounds)

1 Preclinical

Therapeutic Areas:

Amyotrophic Lateral Sclerosis (ALS) Frontotemporal Dementia (FTD) TDP-43 Proteinopathies Neurodegeneration Protein Aggregation Disorders

Druggability Rationale: TARDBP presents significant druggability challenges due to its classification as a transcription factor with intrinsic RNA-binding function, which typically lack well-defined small molecule binding pockets suitable for conventional drug design. However, the target remains tractable given 29 available PDB structures with 0.75 Å resolution, cryo-EM data, and successful proof-of-concept with Tofersen (antisense oligonucleotide), suggesting that indirect modulation or allosteric approaches may overcome the low 0.30 druggability score better than orthosteric inhibition.

Mechanism: RNA-binding and transcription regulation, challenging for small molecule targeting

Drug Pipeline (1 compounds)

1 Preclinical

Known Drugs:

Tofersen (investigational) — ALS

Structural Data:

PDB (29) ✓AlphaFold ✓Cryo-EM ✓

2CQG 2N2C 2N3X 2N4G 2N4H+24 more

UniProt: A0A087WYY0

Binding Pocket Analysis:

TARDBP contains two tandem RNA recognition motifs (RRM1/RRM2) with characteristic β-sheet sandwich folds that bind single-stranded RNA through conserved aromatic residues; high-resolution structures reveal both the RNA-binding cleft and potential allosteric pockets near the linker region between domains, though the primary challenge lies in targeting loss-of-function aggregation and cytoplasmic mislocalization rather than catalytic inhibition.

🧬 3D Protein Structure

🧬 TARDBP — PDB 2N3X Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

Selectivity challenges are moderate since TDP-43 is predominantly expressed in neurons and muscle, reducing potential off-target toxicity in other tissues; however, the RNA-binding domain is shared across multiple RBP families, requiring careful structural selectivity to avoid inhibiting related proteins like FUS or hnRNPs that may compensate for TDP-43 loss.