St. Jude Children’s Research Hospital shared a post on LinkedIn:
“New research from St. Jude Children’s Research Hospital provides insights into G-protein coupled receptor (GPCR) activation, one of the most important mechanisms in cellular signaling and drug targeting. GPCRs are the most common targets of FDA-approved drugs, yet the mechanisms by which different ligands produce varying levels of activation have remained unclear. The findings shed light on how the speed of receptor activation, rather than the final activation state, determines the strength of downstream effects.
The study focused on the mu-opioid receptor, a GPCR central to pain management therapies. By comparing partial, full and super agonists, scientists found the differences in efficacy arise from how quickly each agonist pushes the receptor through its activation steps. Partial agonists kinetically trap the receptor in intermediate conformations, requiring significant energy to proceed, which slows full activation relative to full or super agonists.
Georgios Skiniotis, PhD, director of the St. Jude Center of Excellence for Structural Cell Biology, explained, “We found that for partial agonists of a GPCR, the system slows down as it gets stuck in specific steps while changing conformations during activation. Regardless of how strongly an agonist activates the system, the steps remain the same, but those that are weaker agonists take longer to move through those steps, correlating with their efficacy.”
These findings were supported by cryo-electron microscopy and single-molecule imaging, which enabled the team to capture intermediate states during GPCR-G protein activation. The results demonstrate that full and super agonists allow the receptor to overcome energy barriers quickly, while partial agonists lead to a more rigid structure that becomes trapped, explaining the observed differences in physiological effect.
This research advances our understanding of how distinct agonists tune GPCR responses and opens new avenues for drug development. By leveraging these insights, future therapies may be engineered to maximize safety and efficacy through more precise control of receptor activation dynamics.”
More posts featuring St. Jude Children’s Research Hospital on OncoDaily.