Molecular glue that stabilizes the LRPPRC-MET-G4 interaction complex to drive MET downregulation - PubMed
4 hours ago
- #G-quadruplex
- #MET oncoprotein
- #epigenetic regulation
- Identified a cis-regulatory element in the MET proximal promoter that forms a stable parallel G-quadruplex (MET-G4), which recruits LRPPRC to promote MET transcription.
- Determined the high-resolution NMR solution structure of MET-G4 and characterized LRPPRC's G4-binding domain for MET-G4 recognition.
- Screened a natural product library and found nitidine (NIT) as a MET-G4 stabilizer that acts as a molecular glue, strengthening the LRPPRC-MET-G4 interaction to form a ternary complex.
- This LRPPRC-NIT-MET-G4 complex downregulates MET expression, explaining nitidine's anticancer effects and inhibiting tumor progression in vitro and in vivo.
- The study suggests an epigenetic regulatory mechanism for MET upregulation and a therapeutic strategy for MET-driven tumors using molecular glues targeting the LRPPRC-MET-G4 interface.