International GPCR research collaboration deciphers the structure of active receptors

Breathe, see, hear — the G-protein-coupled receptor (GPCR) family is involved in a variety of physiological processes and is also the cause of various diseases. As a team of scientists led by Professor Ines Liebscher of the University of Leipzig has now discovered, some members of the GPCR family respond to mechanical stimuli. In collaboration with Chinese research groups, they have taken a new step in understanding the mechanism by which this class of receptors is activated. For the first time, they were able to describe the structure of specific active receptors. Their findings have just been published in the journal Nature.

“GPCRs are involved in almost every physiological process in the body. GPCRs allow humans to see, to control their immune system, to direct hormonal balance,” explained Professor Ines Liebscher of the Institute of Biochemistry Rudolf Schönheimer of the Faculty of Medicine, emphasizing: “They have been the focus of our research for many years now, and research on GPCRs is of such exceptional importance because the majority of approved drugs target this family of receptors. GPCRs are receptors that transmit their signals via so-called G-proteins, which is why they are also called G-protein-coupled receptors – or GPCRs for short.

The Leipzig researchers are focusing their work on a particular class of receptors, called adhesion GPCRs. Together with several teams of Chinese scientists, the research groups led by Prof. Ines Liebscher and Prof. Torsten Schöneberg have now been able to describe the structure of special receptor molecules in their active state. These data confirm findings seven years ago at the Leipzig institute that these receptors are activated by an agonist attached within the molecule. Furthermore, the Leipzig researchers showed that mechanical stimuli play a crucial role in activation by the tethered agonist. It is still not fully understood how our body’s own cells are able to interpret mechanics – in the form of vibrations, gravitational forces, relative cell movement or swelling – as a signal. “Our research has established the basis for our Chinese partners to structurally elucidate a scenario of how mechanical stimuli are recognized in the molecule and transmitted as signals,” said Liebscher, a medical scientist and biochemist. “The results can be found in the current study.”

Functional nature of mechanosensitive receptors elucidated

“About a third of the GPCR family are still orphans, which means that their function or activation is unknown. With our current research, we have made a decisive contribution to a better understanding of GPCR structures,” said the co-author. Schöneberg, director of the Rudolf Schönheimer Institute of Biochemistry. “The new study findings are of critical importance when it comes to developing future forms of therapy,” Liebscher concluded. She is a member of the steering committee of the EU-funded COST action Adher’n Rise CA18240, which she successfully obtained in 2019. This network of scientists from 28 European countries aims to promote, stimulate and implement adhesion research G. protein-coupled receptors (aGPCR) “from bench to bedside”. The latest findings and approaches to GPCR research on adhesion will also be presented at the international 4GPCRnet conference, of which Prof. Liebscher is a co-organizer. This high-level meeting will take place from 26 to 29 September 2022 at the Augustusplatz campus of the University of Leipzig.

The current research project is part of the Collaborative Research Center 1423 “Structural Dynamics of GPCR Activation and Signaling”, a research network funded by the German Research Foundation, led by the University of Leipzig and also involving Martin Luther University Halle-Wittenberg, Charité — Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine. Researchers with backgrounds in biochemistry, biomedicine, and computer science collaborate across the boundaries of their respective institutions and disciplines for a comprehensive understanding of GPCR structure and dynamics.

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Material provided by Leipzig University. Original written by Peggy Darius. Note: Content may be edited for style and length.


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