New insights into adhesion GPCRs spark drug design potential

Researchers at the University of Chicago have made a significant breakthrough in understanding adhesion G protein-coupled receptors (aGPCRs), a family of proteins vital for processes such as tissue growth, immune responses, and organ development. By capturing the full structure of aGPCRs and uncovering alternative activation mechanisms, this research opens up new possibilities for the development of targeted drugs.

Adhesion GPCRs, the second-largest family of GPCRs in humans, help cells adhere to one another and transmit signals throughout the body. They play an essential role in various biological processes, and malfunctions in aGPCRs are linked to diseases such as cancer, brain disorders, and growth abnormalities. However, despite their importance, no drugs currently target aGPCRs due to their large, complex structure and the challenges associated with studying them.

“This opens up new opportunities for drugging adhesion GPCRs, because now we are showing that the extracellular region is communicating with the transmembrane region,” said Dr Demet Araç, Associate Professor of Biochemistry and Molecular Biology at the University of Chicago and senior author of the study published in Nature Communications.

A structural milestone

Using cryo-electron microscopy (cryo-EM), the researchers captured the first known structure of a complete aGPCR, including the extracellular region and its interaction with the cell’s transmembrane region. Dr Araç’s lab has been working for over a decade to map the intricate configurations of full-length aGPCRs, finally achieving success with the receptor Latrophilin3, a molecule linked to brain development, ADHD, and several cancers.

Graduate student Dr Szymon Kordon led the effort to stabilise the complex extracellular region for imaging. Collaborating with Dr Antony Kossiakoff at the University of Chicago, the team developed a synthetic antibody to stabilise the receptor, allowing them to capture its full structure using cryo-EM.

Alternative activation mechanisms

The research revealed that the extracellular region of the receptor assumes multiple configurations. These different positions create distinct interactions between the extracellular and transmembrane regions, suggesting a mechanism for receptor activation that does not rely on separating the GPCR Autoproteolysis INducing (GAIN) domain—a process previously thought necessary for activation.

“Different conformational states correlated to different signalling activity of the receptor,” explained Dr Kordon. His work further demonstrated that these configurations allow the receptor to toggle between active and inactive states, providing a potential pathway to regulate their function with precision.

Future of drug design

The implications of this research extend far beyond structural biology. With a clearer understanding of how aGPCRs function, researchers could design drugs that precisely target their extracellular regions. These drugs would avoid binding to other GPCRs, reducing the risk of side effects.

“This could be the future of drugging adhesion GPCRs,” said Dr Araç. “The advantage of this is that extracellular regions are very different from each other, so you can target them with a drug that doesn’t bind to other receptors and cause unwanted side effects.” The study, supported by the National Institutes of Health, the Chicago Biomedical Consortium, and the National Cancer Institute, marks a turning point in exploring aGPCRs as viable drug targets. With 33 aGPCRs identified in humans, the potential for new treatments is significant.

This study was published in Nature Communications.