(MEMPHIS, Tenn. – December 22, 2025) G-protein coupled receptors (GPCRs) are proteins triggered by ligands (protein-binding chemicals) from outside cells to transmit signals inside the cell. These signals are transmitted primarily through the activation of G proteins, which produce various physiological effects. Due to their important role in growth, metabolism and neurotransmitter signaling, GPCRs represent outstanding drug targets, including one-third of Food and Drug Administration (FDA) approved drugs. However, a lack of understanding about how different ligands that bind the same GPCR can cause varying levels of the same effect has stymied drug development. Findings from St. Jude Children’s Research Hospital show that the speed at which different ligands, called agonists, push the mu-opioid receptor, a well-known GPCR and the target of pain management drugs such as morphine and codeine, through its activation steps explains how agonists can affect the same GPCR differently. The findings were published today in Nature.
A kinetic trap is a state in which something, in this case a GPCR, gets stuck in intermediate shapes (conformations) during activation that takes significant energy to get out of. Imagine a small ball rolling down a hill that gets slowed by a small divot, while a different, larger ball may roll all the way down the hill quicker, uninterrupted by the same hole. Most GPCRs start signaling by changing their shape to activate and release a bound G-protein after an agonist binds. These shape changes must cross kinetic traps – divots in the hill on the way to activation – which the study found different agonists can push GPCRs through, just at different speeds, akin to the different sized balls rolling down a hill. The varying rates at which these processes occur explained differences in efficacy even though the end state remains structurally identical.
“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,” said corresponding author Georgios Skiniotis, PhD, St. Jude Center of Excellence for Structural Cell Biologydirector and Department of Structural Biology member. “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.”
“We were able to capture 'molecular movies' of how three very different drugs for the mu-opioid receptor fine-tune their level of signaling at G-proteins,” said first author Michael Robertson, PhD, formerly of Stanford University, now of Baylor College of Medicine. “These insights may help the development of better pain relievers to combat the ongoing opioid epidemic and better GPCR drugs broadly.”
Getting stuck in a kinetic trap
The investigators uncovered the underlying source of variation by obtaining several structures of intermediate states during GPCR-G protein activation. They compared a partial, full and super agonist of the mu-opioid receptor against each other and used cryo-electron microscopy (cryoEM) to capture images of G-protein activation release over time.
“We saw that partial agonists got the GPCR stuck for longer in a ‘kinetic trap,’” Skiniotis said. “Super and full agonists pushed through to G-protein dissociation quickly, but partial agonists spent longer in a pseudo-stable form before G-protein release.” This mechanism was further supported by single-molecule imaging measurements, performed in collaboration with the lab of co-author Scott Blanchard, PhD, St. Jude Single-Molecule Imaging Center director and Department of Structural Biology member, who also leads the St. Jude Collaborative Research Consortium on G protein-coupled receptors.
The scientists found that G-protein activation requires the bound GPCR and agonist complex to overcome energy barriers for several intermediate shape changes. Full and super agonists gave the GPCR the ability to be more dynamic, letting it overcome the energy barriers between these shape changes quickly, with super agonists outstripping full agonists. Partial agonists led to a more rigid structure, which struggled to overcome these energy barriers, becoming especially stuck in a kinetic trap near the end of the process. Notably, partial agonists achieve activation over time, just much slower than full or super agonists, providing a clear explanation for the difference in the strength of their effects.
“We showed that different agonists act like different people pushing a sticky dimmer switch,” Skiniotis said. “All are moving it from off to on, but those of higher strength are pushing it faster, while those of lower strength get slowed or ‘trapped’ along the way where the track is particularly sticky. This understanding may help us better understand how GPCRs function and guide engineering of next-generation drugs that are fine-tuned to maximize safety and maintain efficacy by taking advantage of these dynamics.”
Authors and funding
The study’s other authors are Makaia Papasergi-Scott and Maria Claudia Peroto, Stanford University; Arnab Modak, Miaohui Hu and Ravi Kalathur, St. Jude; Balazs Varga and Susruta Majumdar, Washington University School of Medicine.
The study was supported by grants from the St. Jude Children’s Research Hospital Collaborative Research Consortium on G protein-coupled receptors (GPCR), the National Institutes of Health (R01 DA059978, K99HL16140601 and K99/R00 HD107581), Cancer Prevention & Research Institute of Texas (CPRIT) (RR230042) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
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