Taste, pain, or response to stress — nearly all essential functions in the human body are regulated by molecular switches called G protein-coupled receptors (GPCRs). Researchers at the University of Basel have uncovered the fundamental mechanism how such a GPCR works. Using a method similar to the earth satellite GPS, they could track the motions of a GPCR and observe it in action. Their findings, recently published in Science, provide guidance for designing drugs.
G protein-coupled receptors are embedded in the cell membrane and transmit signals from the outside to the inside of the cell. Because of their vast diversity and crucial role in the body, GPCRs are targeted by many drugs, such as painkillers, heart medications, and even the semaglutide injection for diabetes and obesity. In fact, about one-third of all approved drugs target GPCRs.
New GPS Nuclear Magnetic Resonance (NMR) method reveals receptor function
Despite their importance, it remained a mystery how these receptors work. “We knew little about how GPCRs transmit the information from the various ligands,” says Dr. Fengjie Wu, SNSF Ambizione Fellow at the Biozentrum. “We developed this novel GPS NMR method that allows us to observe how the receptor moves.” A detailed understanding of GPCR function is crucial for developing more effective drugs with fewer side effects.
In their study, the researchers focused on the β1-adrenergic receptor, a GPCR that plays a key role in the cardiovascular system and is targeted by beta-blockers. These drugs are used to treat high blood pressure and cardiovascular diseases. Using the GPS NMR technology, the researchers precisely determined the position of about one hundred sites within this receptor — just like the GPS pinpoints a car’s location — and monitored their motions during activation.
Dynamic receptor: more than just “On” or “Off”
Their findings reveal that the receptor does not simply switch between static “off” and “on” states. Instead, it sits in a dynamic conformational equilibrium between inactive, preactive, and active states. The binding of agonists such as the drug isoprenaline shifts the receptor more towards the active state, while beta-blockers lock it mostly in the inactive state. ” We finally can tell with confidence how the receptor transitions between its functional states,” explains Wu. “We could even define a highly conserved central microswitch that controls these states.”
The researchers also discovered that the signaling output of the receptor can be fine-tuned via very small atomic modifications. “To truly understand how these receptors work, it is essential to go down to the atomic level and to observe the motions in response to perturbations,” says Wu.
Guidance for drug design
Using NMR, the scientistsbridge the gap between the static structures of GPCRs and their function. For the first time, they have been able to track in detail how the receptor dynamically moves during activation. “After twenty years of efforts, we can finally see very fine details of the receptor motions,” says Prof. Stephan Grzesiek. And Wu adds “With these observations, we now understand the basic mechanism how drug binding regulates the receptor,” says Wu. “This knowledge may provide guidance for designing drugs with desired outputs.”
