TGM2

Protein-glutamine gamma-glutamyltransferase 2

Score: 0.640 Price: $0.64 Medium Druggability Status: active Wiki: TGM2

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

260

DEBATES

3D Protein Structure

🧬 TGM2 — PDB 1KV3 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.49

Clinical Stage

Phase II

Target Class

Enzyme

Safety

0.50

Druggability Analysis

Drug Development0.30

Structural Tractability0.85

Target Class0.85

Safety Profile0.50

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (2 compounds)

Therapeutic Areas:

Huntington's disease Neurodegeneration (general) Protein aggregation disorders Neurotoxicity prevention Neuroinflammation

Druggability Rationale: TGM2 is highly druggable (0.75 score) due to its well-characterized catalytic active site, extensive structural data (17 PDB structures at 1.84 Å resolution), and validated precedent with approved cystamine/cysteamine inhibitors. As a soluble enzyme with a defined nucleophilic cysteine catalytic mechanism, it presents clear opportunities for small molecule inhibitor design targeting the active site.

Mechanism: Small molecule inhibitors of transglutaminase enzymatic activity

Drug Pipeline (2 compounds)

Known Drugs:

Cystamine (Clinical trials) — Huntington's disease

Cysteamine (Approved) — Cystinosis

Structural Data:

PDB (17) ✓AlphaFold ✓Cryo-EM ✓

1KV3 2Q3Z 3LY6 3S3J 3S3P+12 more

UniProt: A2A2A0

Binding Pocket Analysis:

The active site features a catalytic triad with a nucleophilic cysteine residue (Cys277) that accepts glutamine substrates, flanked by a putative protein binding groove; crystal structures reveal accommodation for both glutamine donor and lysine/polyamine acceptor substrates, suggesting potential for selective inhibitor design via substrate-site targeting or allosteric modulation near the GTP-binding domain.

🧬 3D Protein Structure

🧬 TGM2 — PDB 1KV3 Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity is a key challenge, as TGM2 is one of nine human transglutaminase isoforms (TGM1-9) with overlapping active site chemistry; off-target activity on TGM1, TGM3, and TGM6 could cause unwanted effects including skin toxicity and immune dysfunction. Achieving isoform selectivity will require targeting TGM2-specific structural features or allosteric pockets distinct from the conserved catalytic site.