The body’s own signaling molecules, and many drugs, often exert their effect via cell surface receptors. These receptors poke through the cell membrane, allowing them to capture information from the extracellular space and bring it inside the cell. Two Berlin Institute of Health (BIH) Visiting Professors, working with partners from China, Denmark and Austria, have now been able to observe for the first time the first steps how a receptor binds with G proteins in the cell’s interior in order to transmit a signal inside the cell. They were able to do this by pooling their expertise in structural biology and high-performance computing. The scientists have now published their findings in the journal Cell. Their work has provided new insight in a key field of biomedical research: the development of better-targeted drugs with fewer side effects. The two BIH Visiting Professors are funded by Stiftung Charité.
Signals are constantly at work inside our bodies. The retina of an eye turns the light it receives into a signal that it transmits to the brain for translation into visual perception. The “stress hormone” adrenaline signalizes danger, making our hearts beat faster and our breathing quicker. Neurotransmitters like serotonin activate neurons in certain parts of our brain, making us feel happy. In all these processes, G protein-coupled receptors (GPCRs) play a crucial role. GPCRs function like little antennae on the cell surface, receiving signals, passing them on, and triggering specific reactions.
Peter Hildebrand, a professor for biophysical computer simulations at Leipzig University’s medical faculty, creates computer simulations to show the action of protein molecules that are linked to the development of disease in the body. “For many years we have wanted to know what happens after the signal meets its receptors on the surface of the cell,” says Hildebrand, who is currently a BIH Visiting Professor. “We are interested in how the receptor transmits the signal inside the cell and what happens next. These initial steps decide what ‘programs’ subsequently run inside the cell and what responses the cell makes to them.” In 2012, cellular physiologist Brian Kobilka of Stanford University won the Nobel Prize in Chemistry for providing answers to precisely these questions. Hildebrand is delighted to be able to work with Kobilka: “We’re fortunate that Brian could come here to Berlin as a BIH Einstein Visiting Professor, to join in our research efforts.”
Hildebrand explains that Kobilka had been able to take a snapshot of a receptor molecule binding to its signaling molecule in the extracellular space and another snapshot of it coupling to G proteins inside the cell. “We had been able to simulate the movement of the molecules in their natural surroundings,” he adds. Hildebrand and Kobilka got together in Berlin to work on their shared interest. “We wanted to understand exactly what is going on beneath the surface of a cell when a signal is being transmitted,” says Hildebrand. But the problem is that these decisive actions happen very quickly – within fractions of a second. “Only working together, we have been able to find out what decides whether or not a signal is passed on and in which direction it is transmitted,” continues Hildebrand. To achieve this, they simulated the movements of the receptor on the computer, subsequently testing the simulation in the lab using structural biological methods to check if it had correctly mirrored the process.
The microscopic, ultrafast movements that Kobilka and Hildebrand were now able to observe for the first time do not only decide what effect a natural or endogenous signal will have: Around a third of drugs also take effect through these receptors and along their signaling chains inside the cell. Such drugs include heart medications, psychopharmaceuticals, and analgesics. How effective these drugs are depends on the particular movements that the drugs trigger when they bind to the receptor,” explains Hildebrand. “The findings we have now published are an important step towards being able to tell if a drug will provoke side effects, because in the future we will know when the drug is triggering a single signaling pathway, or multiple pathways, or perhaps the wrong one, inside a cell.”
Professor Axel Radlach Pries, interim Chairman of the BIH Executive Board and Dean of Charité – Universitätsmedizin Berlin as well as host of the BIH Visiting Professor Peter Hildebrand, expressed his delight at the current publication in the journal Cell: “Research into signal transmission is of utmost importance to medical science and to the BIH’s mission of translating research findings from the lab to the clinic. And it reinforces our belief that it’s a good idea to bring together outstanding minds at the Berlin Institute of Health.”
Stiftung Charité has since 2014 been enabling high-level scientists to do research at the BIH through its Johanna Quandt Private Excellence Initiative. Altogether, 20 Einstein BIH Visiting Fellows and 13 BIH Visiting Professors have come to Berlin since the BIH’s founding – and a few days ago six new BIH Visiting Professors were announced. The aim of the initiative is to give scientists an opportunity to pursue innovative research projects and to help the BIH build a network of contacts with outstanding scientists and their home institutions, thus pushing forward biomedical research in Germany while also enhancing Berlin’s position as a science location.
Link to publication: https://doi.org/10.1016/j.cell.2019.04.021