A study led by researchers at the University of Washington Institute for Protein Design and Skape Bio reported AI-driven de novo protein design of miniproteins that can switch GPCRs on or off with high affinity and selectivity. The work, published in Nature, describes computationally designed miniproteins engineered to recognize receptor states by binding dynamic pockets that shift between active and inactive conformations. The team said they generated agonists for GPCRs linked to itch and pain and antagonists for receptors implicated in cancer, metabolic disease, and migraine. Cryo-EM structures of five designed miniproteins reportedly matched the computational models, supporting the design pipeline’s accuracy. If reproducible across broader GPCR families, state-specific miniproteins could expand targeted modality options beyond conventional antibodies and small molecules for hard-to-drug conformational biology.