G protein-coupled receptors, or GPCRs, sit in the plasma membrane, the boundary that defines the inside and outside of a living cell. They communicate with nearly every physiological process in our bodies — from the ability to see and smell, to sensing of adrenaline, insulin, nutrients and medicines.
A key challenge has been developing molecules that can toggle GPCRs on and off in different contexts. Doing so would not only provide insight into how these receptors control almost every bodily function, but also inroads to medicines for a host of diseases that lack treatments.
The UW Medicine Institute for Protein Design and Skape Bio led a new study showing for the first time that AI can be used to create computationally designed proteins to activate or block GPCRs.
Their findings are published May 21 in Nature.
"Protein design takes our understanding of how proteins fold and reverses it — asking if we can envision, with the aid of AI computing, a new protein that sticks to a target in a purpose-built way," said senior author David Baker, director of the UW Medicine Institute for Protein Design .
"This paper showcases how we can do this repeatedly for different GPCRs in ways that capitalize on their dynamic motion to either activate or inactivate them. The result is a generalized approach to targeting biologically critical receptors," added Baker, who is a professor of biochemistry at the University of Washington School of Medicine and a Howard Hughes Medical Institute Investigator.
The signaling switch of GPCRs sits in deep flexible pockets, the shape of which makes them difficult to target. The team developed specialized design strategies to build miniproteins (proteins with fewer than 100 amino acids) that can slip into these hard-to-access sites. This approach enabled the generation of molecules designed to either activate or block signaling.
By targeting specific active or inactive receptor states, the team designed miniproteins that precisely control GPCR signaling in cells, either turning it on or shutting it down. Structural studies showed that several closely matched their design models. In one mouse study, a designed miniprotein performed comparably to a clinically used drug while showing fewer side effects.
"Existing drugs such as antibodies bind to but often fail to activate or block GPCR signaling," said Edin Muratspahić, an Institute for Protein Design postdoctoral research scholar and a first author of the study. "Seeing computationally designed miniproteins not only bind but actually control GPCR signaling in living cells was a defining moment for me."
To accelerate the discovery of designed proteins targeting GPCRs, the researchers also invented a new screening system. Traditional screening is difficult for these receptors because many methods require that they be purified, stabilized, or otherwise altered in ways that can change their signaling. By working directly in living human cells, the new system can test tens of thousands of proteins against GPCRs while keeping the receptors in the cell membrane.
The Institute for Protein Design is committed to translating its rapidly advancing discoveries in AI-driven scientific research into solutions that improve lives. Skape Bio was founded to revolutionize the development of GPCR therapeutics with designed biologics.
Built by founders from the Baker Lab and the BioInnovation Institute ecosystem in Copenhagen, the company unifies GPCR-tailored AI design, a proprietary native-receptor screening system in human cells, protein production, and pharmacology into a single platform. Its goal is to create drug candidates for metabolic, inflammatory, and neurologic diseases by targeting GPCRs that have remained largely inaccessible to conventional drug discovery.
"The methods we are sharing in this new study form the roadmap for achieving all-computational design of protein ligands for any GPCR," said Christoffer Norn, corresponding author and co-founder of Skape Bio. "One of the great strengths of the Institute for Protein Design is its capacity to drive its research quickly from the university setting to start-ups that can carry that work forward into real-world impact."
"At Skape Bio," added Norn, "we are achieving this impact by maturing the methods and approaches necessary to deliver therapies for patients across a wide range of diseases where GPCRs are known to be effective targets, but where medicines have not previously been available."
Other study collaborators included the BioInnovation Institute, Monash University, the MRC Laboratory of Molecular Biology, Johns Hopkins University, the University of North Carolina, Novo Nordisk, Lundbeck, the University of Oregon, the Indian Institute of Technology Kanpur, and Eurofins DiscoverX.
In addition to structural validation, the work reports selectivity profiling, pharmacokinetic optimization, and in vivo data supporting the therapeutic potential of designed GPCR modulators.
The work was funded by: Austrian Science Fund Erwin Schrödinger Program (J-4663); BioInnovation Institute Foundation (BII22SG1021010, BII24SG1021475, II24SG1022030); Novo Nordisk Foundation (NNF18OC0030446); Howard Hughes Medical Institute (GR020267); Novo Nordisk (GR018355); Defense Threat Reduction Agency (HDTRA1-21-1-0038); Microsoft (GF117374); The Audacious Project at the Institute for Protein Design (PG117878, PG117879, PG117866); The Nordstrom Barrier Institute for Protein Design Directors Fund (GF124659);
The Open Philanthropy Project Universal Flu Vaccine Fund (GF129461); The Open Philanthropy Project Improving Protein Design Fund (GF129460); The Wu Tsai Protein Innovation Fund (GF151772); Cancer Research Grand Challenge provided by Cancer Research UK (GR050755); Department of Defense and Defense Threat Reduction Agency (HDTRA1-21-1-0007; GR013444); National Institutes of Health's National Cancer Institute (R01CA240339, GR00923, K99-CA293001); National Institutes of Health's National Institute on Aging (R01AG063845, GR009173, K99-CA293001); U.S. Department of Energy, Office of Science, including resources of the National Energy Research Scientific Computing Center (BER-ERCAP0022018); National Institutes of Health's National Institute on Drug Abuse (R01DA055656); National Institute of Mental Health Psychoactive Drug Screening Program; National Health and Medical Research Council of Australia Investigator (2025694, 2026300); National Science Foundation (2143160); Department of Defense (W81XWH-21-1-0891); National Institutes of Health's National Institute of Dental and Craniofacial Research (R21DE031436); CureSearch for Children's Cancer award; Senior Fellowship of the DBT Wellcome Trust India Alliance (IA/S/20/1/504916); ANRF (ANRF/ARG/2025/007393/LS); Department of Biotechnology (BT/PR53019/MED/30/2528/20); and Lady Tata Memorial Trust.
Several of the reserchers declared competing interests in their May 21 Nature paper, De novo design of GPCR binders.
This news release was written by Skape Bio, UW Medicine Institute for Protein Design, and the HAUS agency.
