Spaces Between GPCRs Assist in Cellular Messaging

G protein-coupled receptors, or GPCRs, play a vital role in immunology and drug discovery research for their signaling abilities to other cell types. From hormones and textures to odors and temperature, GPCRs allow us to make sense of our environment and effectively transmit information from outside the cell to the inside. A research team led by Prof. Stephan Grzesiek, with collaborators from Biozentrum of the University of Basel and the Paul Scherrer Institute, has discovered that GPCRs are surrounded by empty cavities essential for cell signaling. These findings reveal novel insight into potential new routes for drug development.

The team, whose work was published in Nature Chemistry, utilized cutting-edge technology to understand the architecture of different GPCRs, paying particular interest to their shared similarities. “Our aim is to understand at the atomic level how GPCRs transmit signals,” says Dr. Layara Abiko, co-director of the study. “For many years, we have therefore been studying the β₁-adrenergic receptor, a GPCR that prepares the body for fight or flight.” 

Using high-pressure NMR and x-ray scattering on receptor crystals in xenon gas, the team could get a clearer picture of these receptors. ”Previously, it was assumed that the cavities inside the receptor are filled with water. We have now revealed that some of them are empty,” says Abiko. These open spaces, or “voids,” assist in GPCR conformational changes, which are vital for initiating the body’s fight or flight response.

The team was able to localize two empty cavities, one of which was effectively filled by cholesterol, another essential cell membrane component. The cholesterol molecules act as a “wedge,” blocking the receptor from changing its shape to a fully active state. “Blocking this void obstructs the subtle but essential movements required to activate the GPCR,” states Abiko. “We think this wedge effect could be another layer of receptor regulation.”

In traditional drug discovery research, classic drug binding sites are similar among GPCR subclasses. Due to the vast nature of GPCRs available in the body, often, this site-binding is non-specific and results in unwanted side effects. However, these empty spaces between these receptors differ considerably between GPCRs, even those from the same subclass. These findings suggest a new potential drug targeting mechanism with higher affinity and fewer unwanted side effects. “In this way, you may design drugs that are highly specific for one receptor,” explains Abiko. 

This new approach shows promise for discovering unconventional drug binding sites, even those that highly differ between receptors. These findings may assist in the screening process for new therapeutics, saving scientists time and resources in their efforts to create new medications.