De novo design of miniproteins targeting GPCRs
Nature • • health
Key Points:
- Researchers have developed computational de novo design methods combined with a high-throughput microscopy-based screen to create GPCR-binding miniproteins with high affinity, potency, and selectivity.
- The designed miniprotein agonists effectively activate receptors involved in itch and pain, while antagonists inhibit receptors linked to cancer, metabolic disorders, and migraine.
- Cryo-electron microscopy structures of five receptor-bound designs closely match the computational models, validating the design approach.
- One designed chemokine receptor antagonist demonstrated in vivo mobilization of hematopoietic stem and progenitor cells comparable to a clinically used drug but with fewer side effects.
- This work advances the ability to design targeted protein modulators for GPCRs, which are critical drug targets but have been difficult to modulate due to their membrane-bound, dynamic nature.