Bifunctional OGTACs steer OGT to install O-GlcNAc on chosen proteins
- OGT/OGA inhibition affects thousands of substrates, so protein-specific O-GlcNAc functions are hard to assign; OGTACs address this by recruiting OGT to a chosen protein.
- Each OGTAC joins an OGT-engaging element, a linker and a target-recognition motif, and can partly bypass TPR-domain substrate recognition.
- Productive O-GlcNAc writing needs proper ternary-complex formation and noninhibitory OGT binding, while the target-recognition motif sets targetable scope and selectivity.
- Local installation is linked to changes in protein turnover, signaling and transcription.
💡 Points
The OGT-binding warhead is the make-or-break piece here: if it inhibits OGT, you lose the very activity you're trying to redirect, so noninhibitory binders are the real SAR hurdle, much as with E3 ligands in degraders. I also like that the target-recognition motif, not OGT's TPR domain, sets selectivity, which makes this modular. It's an Accounts-level overview, so I'd want to see how well the chimeras hold up across targets before getting excited.
Chemically Induced Proximity for Targeted Protein O-GlcNAcylation ↗