A new study published May 21 in Nature details how computationally designed miniproteins can effectively activate or block G protein-coupled receptors (GPCRs). The research was led by the UW Medicine Institute for Protein Design and Skape Bio.
Key Findings
The team used AI to design miniproteins (fewer than 100 amino acids) that target GPCR signaling pockets.
These designed miniproteins were able to either turn on or shut down GPCR signaling in cells. Structural studies confirmed the designed proteins closely matched their original computational models.
In a mouse study, a designed miniprotein performed comparably to a clinical drug with fewer side effects.
Researchers also developed a new screening system that tests proteins against GPCRs in living human cells, avoiding the need for receptor purification.
Background
GPCRs are membrane proteins involved in many physiological processes. Their flexible binding pockets make them particularly difficult to target with conventional drugs.
The study was funded by multiple organizations including the Austrian Science Fund, BioInnovation Institute, Novo Nordisk Foundation, Howard Hughes Medical Institute, and others.
What the Researchers Said
"The work demonstrates a generalized approach to targeting GPCRs by capitalizing on their dynamic motion."
— David Baker, Senior Author
"Seeing designed miniproteins control GPCR signaling in living cells was a defining moment."
— Edin Muratspahić, First Author
"The methods provide a roadmap for all-computational design of protein ligands for any GPCR."
— Christoffer Norn, Corresponding Author