G protein-coupled receptors (GPCRs) are among the most widely targeted proteins in modern medicine, but their complex structure makes them difficult to selectively modulate. Researchers at the University of Washington School of Medicine’s Protein Design Institute and Scape Bio now report the design of AI-assisted miniproteins that can activate or inhibit selected GPCRs.
Published in naturethis study describes a computational approach to design proteins that can recognize specific GPCR conformations and control receptor activity.
Targets major classes of membrane proteins
GPCRs are embedded within cell membranes and control a wide range of biological processes, including vision, smell, metabolism, and hormonal signaling. As a result, they represent one of the most important classes of drug targets.
However, their structural flexibility and ability to adopt multiple active and inactive states continue to pose challenges for drug developers seeking to selectively modulate receptor activity. To address this, researchers sought to design proteins that could recognize the conformation of specific receptors.
Researchers used computational design techniques to create mini-proteins containing fewer than 100 amino acids that can access deep receptor pockets that are inaccessible to traditional drug discovery techniques.
By targeting specific active and inactive receptor states, proteins can activate signaling pathways or prevent signaling from occurring.
Explaining the rationale behind this approach, David Baker, director of the Protein Design Laboratory at the University of Wisconsin Medical Research Institute, said: “Protein design requires an understanding of how proteins fold and how to reverse them. With the help of AI computing, we ask whether we can imagine new proteins that stick to their targets in a tailored way.”
“This paper shows how this can be done repeatedly for different GPCRs, using their dynamic movements to activate or inactivate them. The result is a generalized approach to target biologically important receptors.”
Structural studies confirmed that several of the designed proteins closely matched the intended model. A mouse study found that an engineered miniprotein performed as well as drugs used in the clinic, but with fewer side effects.
Screening for receptors in their native membrane environment
In addition to designing mini-proteins, the researchers developed a screening platform that allows them to directly test tens of thousands of candidate proteins in living human cells.
Traditional GPCR screening approaches often require purification, stabilization, or other modification of receptors prior to analysis, a process that can alter receptor behavior and impact signaling activity. The new platform allows for the screening of engineered proteins while the receptor remains embedded within the cell membrane, providing a more biologically relevant testing environment.
Expanding opportunities for GPCR therapeutics
The researchers suggest that this platform could have potential applications in a wide range of therapeutic areas, including metabolic, inflammatory and neurological diseases.
“Seeing that computationally designed mini-proteins not only bind to but actually regulate GPCR signaling in living cells was a defining moment for me,” said Edin Muratspahic, a postdoctoral fellow in the UW Medicine Institute for Protein Design and lead author of the study.
The research team also sees broad potential for applying computational protein design across the GPCR family.
“The methods we share in this new study form a roadmap for achieving all-in silico design of protein ligands for any GPCR,” said Christoffer Norn, corresponding author and co-founder of Skape Bio.
The researchers believe that the combination of computational protein design and natural cell screening could support the development and evaluation of future GPCR-targeted therapies. This discovery could also aid efforts to develop more selective modulators of GPCRs, which remains a major focus of drug discovery research.
Researchers interested in membrane protein analysis can learn more in this webinar From expert tasks to lab routines – simplifying membrane protein purification and analysiswe explore automated workflows and technologies designed to simplify membrane protein purification and stability analysis while preserving native protein structure.
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