UW Medicine designs AI miniprotein GPCR switches

UW Medicine and Skape Bio said on May 21 that researchers had used AI-guided protein design to create miniproteins that can switch G protein-coupled receptors, or GPCRs, on and off. The work was published the same day in Nature in a paper titled “De novo design of miniproteins targeting GPCRs.” UW Medicine said the study showed, for the first time, that computationally designed proteins could be built to activate or block GPCRs, a large class of cell-surface receptors central to drug discovery. ### Why are GPCRs such a big target in the first place? GPCRs sit in the plasma membrane and help cells respond to signals tied to vision, smell, adrenaline, insulin, nutrients and medicines, according to UW Medicine. Nature and other GPCR reviews describe the receptor family as one of the largest and most important target classes in drug development. (newsroom.uw.edu) UW Medicine said the design challenge is that GPCR signaling depends on deep, flexible pockets and shifting receptor shapes, which make it hard to build proteins that reliably turn signaling up or down. David Baker, senior author and director of the UW Medicine Institute for Protein Design, said the team aimed to use AI computing to imagine new proteins that stick to a target in a purpose-built way. (newsroom.uw.edu) ### What exactly did the researchers design? The paper describes “miniproteins” with fewer than 100 amino acids that were engineered to fit into hard-to-reach GPCR sites and either activate or block signaling. UW Medicine said the team designed the molecules to recognize specific active or inactive receptor states, letting them work as agonists or antagonists depending on the target. (newsroom.uw.edu) The bioRxiv version of the study said the group paired computational de novo design with a high-throughput, microscopy-based “receptor diversion” screen. That screen was used to generate agonists for receptors including MRGPRX1, NK1R and CCR5, and antagonists for CXCR4, CCR5, OXTR, GLP1R, GIPR, GCGR, PTH1R and CGRPR. ### How did they test whether the designed proteins worked? Structural studies showed that several of the designed miniproteins matched the researchers’ design models closely, UW Medicine said. (newsroom.uw.edu) The preprint said cryo-electron microscopy found atomic-level agreement between designed and experimentally determined structures for CGRPR- and CXCR4-bound antagonists and an MRGPRX1-bound agonist. (biorxiv.org) Edin Muratspahić, a postdoctoral research scholar at the Institute for Protein Design and a first author, said existing drugs such as antibodies can bind GPCRs but often do not activate or block signaling effectively. UW Medicine said the new approach was built to produce miniproteins with high affinity, potency and selectivity. ### Did the study go beyond cell experiments? UW Medicine said one mouse study found that a designed miniprotein performed comparably to a clinically used drug while producing fewer side effects. (newsroom.uw.edu) The release did not, in the excerpt available publicly, specify the drug in that summary passage, but it presented the animal result as an early proof that the designed proteins could extend beyond in vitro receptor assays. (eurekalert.org) Nature listed Edin Muratspahić, David Feldman and David Baker among the paper’s lead authors, and the bioRxiv record said several authors were listed on University of Washington innovation records and related provisional patent applications tied to the discoveries. The paper was published on May 21, and UW Medicine’s release identified the work as led by the Institute for Protein Design and Skape Bio. (nature.com) (newsroom.uw.edu)