De novo design of GPCR exoframe modulators - PubMed
6 days ago
- #GPCR
- #drug discovery
- #allosteric modulation
- GPCRs are key therapeutic targets traditionally modulated via orthosteric sites.
- Allosteric modulation is emerging as a novel strategy in GPCR drug discovery.
- GPCR exoframe modulators (GEMs) are de novo designed proteins targeting GPCR transmembrane domains.
- GEMs were designed using a hallucination-like approach with three structural prompts.
- Four GEMs were studied on the dopamine D1 receptor, showing diverse allosteric modulation effects.
- GEMs include agonist-positive allosteric modulator, negative allosteric modulator, and biased allosteric modulator types.
- Ago-PAM GEM can restore activity in D1 receptor loss-of-function mutants, indicating therapeutic potential.
- Deep learning-based design of GEMs showcases advancements in membrane protein engineering.