How it works: the dynamic G protein-coupled receptor
A GPS-like technique has been used to track G protein-coupled receptor movement, revealing how these essential receptors function.
Although G protein-coupled receptors (GPCRs) are crucial to the regulation of most functions in the human body, very little is known about how they work. In a new study, researchers at the Biozentrum of the University of Basel (Switzerland) used a recently developed technique to track GPCR movement, offering greater insight into receptor function and guidance for drug design.
GPCRs are embedded in the cell membrane and are responsible for transmitting signals inwards across the membrane. Their diversity and essential role in the body make them a common drug target for a range of medications, including painkillers and heart medications. In fact, one-third of approved drugs target GPCRs. However, despite their importance, the mechanism by which GPCRs function has remained unknown.
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To reveal more about GPCR function, the current research team used a GPS nuclear magnetic resonance (NMR) technique to atomically monitor the conformational changes of the β1-adrenergic receptor, a GPCR involved in the cardiovascular system that is targeted by beta-blockers to treat high blood pressure and cardiovascular disease. They assigned 81 backbone amide NMR signals to sites within the β1-adrenergic receptor. Using this GPS NMR technique, they were able to visualize the conformational changes that occur in the receptor in response to ligand binding.
They found that the β1-adrenergic receptor is dynamic, moving between four distinct conformations – inactive, preactive, active and transducer-bound active – in response to agonists and beta-blockers. “We finally can tell with confidence how the receptor transitions between its functional states,” explained first author Feng-Jie Wu. They also discovered that the signaling output of the receptor can be fine-tuned via small atomic modifications.
By monitoring GPCR movement, the team has brought these static structures to life, offering new perspectives on receptor function and drug design. “With these observations, we now understand the basic mechanism how drug binding regulates the receptor,” concluded Wu. “This knowledge may provide guidance for designing drugs with desired outputs.”
