G-protein coupled receptors (GPCRs) are pivotal proteins that play a crucial role in transmitting signals from outside the cell to the inside. These signals, primarily channeled through the activation of G proteins, lead to various physiological effects. Given their significant role in processes such as growth, metabolism, and neurotransmitter signaling, GPCRs are prime targets for drug development, with approximately one-third of Food and Drug Administration (FDA) approved drugs targeting these receptors. However, a persistent challenge in drug development has been understanding how different ligands binding to the same GPCR can produce varying levels of activation.
Recent findings from St. Jude Children’s Research Hospital, published in Nature, have shed light on this complex mechanism. The study reveals that the speed at which different ligands, known as agonists, activate the mu-opioid receptor—a well-known GPCR targeted by pain management drugs like morphine and codeine—explains the varying effects of these agonists. This breakthrough could have significant implications for the development of more effective drugs.
Understanding the Kinetic Trap
The concept of a “kinetic trap” is central to these findings. A kinetic trap occurs when a GPCR gets stuck in intermediate shapes, or conformations, during activation, requiring significant energy to proceed. To visualize this, imagine a small ball rolling down a hill that gets slowed by a small divot, while a larger ball might roll down uninterrupted. Most GPCRs initiate signaling by changing shape to activate and release a bound G-protein after an agonist binds. These shape changes must navigate kinetic traps—akin to divots—on the path to activation. The study found that different agonists push GPCRs through these traps at varying speeds, much like balls of different sizes rolling down a hill.
“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 Georgios Skiniotis, PhD, corresponding author and director of the St. Jude Center of Excellence for Structural Cell Biology.
Implications for Drug Development
The findings have profound implications for drug development, particularly in the context of the opioid epidemic. By capturing “molecular movies” of how different drugs for the mu-opioid receptor fine-tune their signaling at G-proteins, researchers have gained insights that could lead to better pain relievers and more effective GPCR-targeted drugs.
Using cryo-electron microscopy (cryoEM), the researchers were able to capture images of G-protein activation over time, comparing partial, full, and super agonists of the mu-opioid receptor. The study showed that partial agonists got the GPCR stuck longer in a kinetic trap, while super and full agonists pushed through to G-protein dissociation more quickly. This mechanism was further supported by single-molecule imaging measurements.
“We showed that different agonists act like different people pushing a sticky dimmer switch. 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,” Skiniotis explained.
Future Directions and Broader Impact
The study’s insights could guide the engineering of next-generation drugs that maximize safety and maintain efficacy by exploiting these dynamics. Understanding how GPCRs function at a molecular level provides a roadmap for developing drugs that are finely tuned to their targets.
The research was a collaborative effort, with contributions from Makaia Papasergi-Scott and Maria Claudia Peroto of Stanford University, Arnab Modak, Miaohui Hu, and Ravi Kalathur of St. Jude, and Balazs Varga and Susruta Majumdar of Washington University School of Medicine. The study was supported by grants from the St. Jude Children’s Research Hospital Collaborative Research Consortium on GPCR, the National Institutes of Health, the Cancer Prevention & Research Institute of Texas, and the American Lebanese Syrian Associated Charities (ALSAC).
As the scientific community continues to explore the intricacies of GPCR activation, these findings represent a significant step forward in understanding and potentially overcoming the challenges of drug development. The hope is that this research will lead to more effective treatments for a variety of conditions, ultimately improving patient outcomes worldwide.
