New study reveals ‘droplet’ mechanism behind key drug targets

A study published in Nature by researchers at Duke University School of Medicine identifies a new way that G protein–coupled receptors (GPCRs) — targets of roughly one-third of FDA-approved drugs — control signaling in cells.

The team found that β‑arrestin proteins, which regulate GPCR activity, can assemble into liquid-like clusters known as condensates both at baseline and near activated receptors. These droplet-like structures act as hubs that organize signaling molecules in space and time.

“Our work shows that these receptors signal in a way we didn’t fully appreciate before,” said senior author Sudarshan Rajagopal, MD, PhD, associate professor of medicine. “That’s important because it suggests new, potentially druggable ways to target GPCR signaling.”

Using imaging, protein interaction assays, and functional studies, the researchers, including MD-PhD student Preston Anderson, who conducted the work for his PhD thesis, showed that disrupting these condensates altered GPCR signaling and receptor internalization, linking the structures directly to function.

The findings help explain how just two β‑arrestin proteins can regulate hundreds of GPCRs and point to condensates as a new mechanism for fine-tuning cellular communication.

Because GPCRs are involved in conditions ranging from shock to heart disease and asthma, the study suggests new strategies for designing more targeted therapies.

Funding: The American Heart Association, the Mandel Foundation, and the National Institutes of Health.

Other Duke Authors: Adam Kaakati, Juliana Alfonso-DeSouza, Alejandra Patino, Andrew Ahn, Chanpreet Jassal, Samuel Liu, Biswaranjan Pani, Athmika Krishnan, Oscar Chen, Joseph Strawn, and Joshua C. Snyder.