CRC 1423 was approved by the German Research Foundation (DFG) in 2020 following an application by Leipzig University. It brings together 19 individual projects. And not only internally at our university, but also with other renowned institutions, such as the Charité in Berlin, the Max Delbrück Center for Molecular Medicine, the University of Düsseldorf and the Martin Luther University Halle-Wittenberg (MLU). Professor Hildebrand emphasises that the scientists involved are doing basic research, but not just that.
The medical scientists are on board because these receptors are also highly relevant to disease. “For example, many mutations are known to cause obesity. So you then work with real patient cohorts and investigate what actually happens with such a mutation. And we are investigating what triggers these mutations at the atomic level.” According to Hildebrand, although GPCRs have been the subject of research for decades, many fundamental aspects are still not understood. One of the main reasons is that these receptors are flexible, meaning that they change their structure depending on their function.
How do drugs bind to receptors?
This is set to change, thanks in part to CRC 1423, which is led by biochemistry professor Annette Beck-Sickinger. In collaboration with a number of experts, the researchers hope to elucidate dynamic structural features and their consequences for receptor function. For drugs such as painkillers, it is important to know which receptors they bind to and how they cause their effects. Ultimately, it is only the dynamic properties of the receptors that can explain how they work.
“These dynamics play a key role in answering the question of how strongly a drug will ultimately bind to and activate the cell exterior of specific receptors. And also why the receptor then docks with one G protein on the inside of the cell, but not with another.” In the end, this would determine how the cell responds to a certain compound, such as a drug. Some reactions are beneficial. Others are not from a pharmacological or physiological point of view. Professor Hildebrandt is delighted: “We are on the right track and are making progress.”
Professor Jens Meiler is also optimistic about the CRC’s preliminary findings. His research at the Institute for Drug Discovery combines computational and experimental methods to better understand proteins and how they interact with drugs and other biomolecules. The two professors are approaching their goal from different directions, but they are discovering more and more common ground. “Peter and I complement each other perfectly. While Peter can understand the movement of receptors in detail, my lab is developing computer algorithms to eventually discover new compounds. We will be working closely together in the future, especially in the new field of artificial intelligence for studying GPCRs,” says Professor Meiler.
Combining the best of both worlds
“Jens is particularly interested in this side, so where the drugs bind. This is important when it comes to designing new drugs. And I’m very interested in how the signal actually gets from there into the cell and how that leads to very specific signalling pathways being triggered.” According to Professor Hildebrand, the methods used by each of them had been separate from each other for a long time.
His biophysical methodology is based on calculating the dynamics of processes at the atomic level using highly sophisticated methods. The technique used by Professor Meiler, on the other hand, is a bioinformatics method that makes it possible, for example, to test the pharmacological properties of millions of potential compounds in a very short space of time. “So far, dynamics has played a rather subordinate role. And now we are both looking beyond our respective horizons and developing new digital tools together to combine the best of both worlds.”
And it has taken less than three years to see the first results: “It is not yet the case that tomorrow we will be at the point where everything is understood in detail and a new drug is on the table. This still requires a lot of joint effort. But through the interdisciplinary research work in the CRC, we are getting better and better at understanding the role of dynamics in the way receptors work.” And the professor believes that this is definitely something to build on.