The Collaborative Research Center (CRC) 1423 “Structural Dynamics of GPCR Activation and Signal Transduction” under the leadership of biochemists Prof. Dr. Annette Beck-Sickinger and Prof. Dr. Torsten Schöneberg from the Leipzig University is continuing into its second funding phase. This was announced today (24.11.2023) by the German Research Foundation (DFG). From January 2024, the research network, which also includes Charité – Universitätsmedizin Berlin, Heinrich Heine University Düsseldorf and Martin Luther University Halle-Wittenberg, will run for another four years. “The focus is on G protein-coupled receptors, GPCRs. We are investigating how they function and their complex interactions in the human body in order to develop new active substances and therapeutics. I am delighted that we can intensify the work we have successfully begun,” says CRC spokesperson Annette Beck-Sickinger.
Mode of action of GPCRs and application in medicine
GPCRs are a large family of receptors located in the cell membrane of almost all living organisms. Responsible for cell communication, they act like sentinels between cells, ready to recognize specific signals and transmit them into the cell environment. There, they trigger a specific reaction in the cell or initiate an internal signal chain and thus play a key role in signal transmission. Without GPCRs, for example, we would not be able to see, smell or taste sweets, and communication between cells, for example in the brain, would also break down.
GPCRs interact with various molecules, so-called ligands (messenger substances), which themselves cannot penetrate the cell membrane and are therefore dependent on a receptor. Their binding changes the structure of the receptor’s protein chain protruding into the cell. This dynamic enables the recognition and activation of intracellular partner molecules, such as G-proteins or arrestin, a protein that plays an important role in the processing of light stimuli in the human eye, which in turn are further processed inside the cell.
As true universal geniuses of signal transmission, GPCRs play a decisive role in drug research. Just over 30 percent of all approved drugs – for example Vomex for nausea, Cetirizine for allergies or Sumatriptan for migraines – act via the biological processes of these receptors. However, a large part of their potential has so far remained untapped, as the complex interplay between ligands, GPCRs and intracellular signaling molecules has been insufficiently researched.
The scientists want to decipher precisely these various highly dynamic states, which differ in their functions. They are paying particular attention to peptide receptors and adhesion GPCRs, as little is known about their mechanisms of action. They compare their findings on the structural dynamics of these receptors with well-researched adrenergic (reacting to adrenaline) and muscarinic (reacting to the mushroom toxin muscarin) acetylcholine receptors. From this, they hope to derive and understand general mechanisms and differences between the various groups.
Results to date
CRC researchers from the life sciences, medicine, pharmacy and bioinformatics have already gained significant insights that are inspiring pharmacological drug research. A unique, synergistically combined mix of different methods – such as the development of specific ligands, crystallographic analyses, cryo-electron microscopy, NMR (nuclear magnetic resonance)-based structural analyses, mutagenesis, functional analyses, fluorescence-based methods and computer-based molecular modeling – was and is the decisive factor.
“So far, our research results have been published in over 120 publications. We have been able to contribute significant structural data, in particular for the neuropeptid Y and melanocortin. We have also been able to explain the binding behavior between ligands and allosteric modulators and
antagonists in more detail,” says Annette Beck-Sickinger. “The physiological signals and molecular functions of many of these receptors were previously not understood and could already be clarified in the first funding period. Thanks to the collaboration of several groups within the CRC and with international cooperation partners, the identification and structural characterization of previously unknown mechanoreceptors (so-called adhesion GPCRs) was achieved. These receptors play a decisive role in cell-cell and cell-environment interactions and have a high potential as tumor markers and targets for future cancer therapies. It also appears that the signal mediation of GPCRs within a cell is spatially highly organized and thus triggers different cellular responses depending on the signal and signal strength – a mechanism that is still poorly understood and therefore used
therapeutically,” adds Torsten Schöneberg.
Future research questions, growing expertise and structural development
While the focus in the first funding period was more on the characterization of GPCRs, the next four years will focus on the dynamics. “We want to elucidate the structural dynamics in different activation states that are linked to GPCR functions. We will compare the mechanisms of peptide GPCRs and adhesion GPCRs with those of well-characterized receptors in order to identify common principles as well as differences between the receptor groups and classes. Novel aspects of signaling dynamics and protease-activated receptors will also be included in the analysis. The structural dynamics of GPCR activation and the modulation of receptor activation and signal selectivity will be the central research questions,” says Annette Beck-Sickinger.
With the second funding period, new sub-projects with methodological enhancements and, in particular, under the leadership of young female scientists are starting their work. In future, for example, GPRC protein dynamics can be investigated using EPR spectroscopy. “A Collaborative Research Center like this enables interdisciplinary collaboration beyond the boundaries of one’s own discipline. Our young scientists in particular benefit from this. They are required to understand the overall context and at the same time have access to numerous new methods and processes,” explains Annette Beck-Sickinger. Particularly noteworthy is the intensive research cooperation with Vanderbilt University in Tennessee (USA), which has excellent research interfaces and is integrated into the qualification program of the integrated graduate school of the SFB1423.
Katrin Henneberg/Anett Albrecht