Breaking the Code: Complete Structure of Adhesion GPCRs Uncovered
Researchers at the University of Chicago have made a groundbreaking discovery that could revolutionize the development of new drugs. They have successfully determined the complete structure of adhesion G protein-coupled receptors (aGPCRs) – a family of proteins crucial for vital processes like cell growth, immune response, and organ development.
This milestone unlocks new possibilities for targeted therapies by shedding light on alternative activation mechanisms of these complex proteins.
GPCRs are proteins embedded in cell membranes that play a key role in the mechanisms of nearly 35 percent of FDA-approved drugs. Unlike other GPCRs, adhesion GPCRs (aGPCRs) have a distinctive large extracellular region that extends beyond the cell membrane into the space outside the cell. This external region binds to molecules and other cell receptors, triggering communication pathways within the cell.
A Structural Milestone
The structure of a complete aGPCR, including the extracellular region and its interaction with the cell’s transmembrane region, has never been captured before. This research, led by Dr. Demet Araç, Associate Professor of Biochemistry and Molecular Biology at the University of Chicago, focused on Latrophilin3, a receptor linked to brain development, ADHD, and several cancers.
Graduate student Dr. Szymon Kordon played a crucial role in stabilizing the complex extracellular region for imaging. Collaborating with Dr. Antony Kossiakoff at the University of Chicago, the team developed a synthetic antibody to stabilize the receptor, enabling them to capture its full structure using cryo-electron microscopy (cryo-EM).
Alternative Activation Mechanisms and Future Drug Design
This breakthrough not only unveils the aGPCR structure but also reveals new activation mechanisms. These findings are crucial for designing targeted drugs. By understanding these mechanisms, researchers can develop drugs that specifically bind to the extracellular regions of aGPCRs, minimizing side effects associated with targeting other receptors.
“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.”
A New Era of Targeted Therapy
This National Institutes of Health, Chicago Biomedical Consortium, and National Cancer Institute-supported research marks a significant leap forward in exploring aGPCRs as viable drug targets. With 33 aGPCRs identified in humans, the potential for new treatments addressing various diseases is vast.
This study, published in Nature Communications, opens up exciting possibilities for future drug development and personalized medicine.