Structural Biology
The Structural Biology division, led by Prof. Dr. Arne Möller, uses cryo-electron microscopy to determine the atomic structure of proteins and their molecular dynamics. It is particularly interested in transmembrane transporters, which are of great importance for the development of broad-spectrum resistance.
Cells and their membranes are filled with a plethora of different proteins, each fulfilling a dedicated purpose. Together, they are responsible for all cellular functions, fundamental to life.
The lab's vision is to obtain high-resolution movies of membrane proteins in action
In Nature, form (or structure) follows function. This applies to our eyes and hands just like it does for proteins. Thus, an understanding of the protein structure provides priceless information about its function.
Conceptually, proteins are nanomachines with mechanical components such as gears, joints, and pistons that operate in motion to fulfil specific functions. Observing such a machine at rest only provides a small aspect of its functional mechanism. Only a movie of the running engine with annotated frames reveals how the components act together in motion.
Cryo-electron microscopy
Our primary tool for analyzing molecular machines is cryo-electron microscopy (cryo-EM), which was awarded the Nobel Prize in 2017. The small size of proteins and the low signal-to-noise ratio in cryo-EM require sophisticated approaches for structure determination. Hence, in the past, dynamic proteins were stalled, which dramatically helped their analysis but also obscured their mechanism.
Our landmark study, published in 2019, challenged this paradigm. By deliberately activating an ATP-binding cassette (ABC) transporter before imaging, we discovered a previously unknown conformation that represents the missing link in the transport sequence. In our data, each conformation corresponds to an individual step in the transporter's working cycle. Some states appear more frequently than others, providing essential clues about their relative durations. Our turnover approach has become state-of-the-art and is widely used by numerous groups for various transporters and other macromolecular complexes.
Membrane transporter
We now apply this technology to decipher the molecular mechanisms, underlying the translocation of small molecules across membranes. We mainly focus on ABC transporters; a large group of proteins present in all kingdoms of life. They utilize the energy stored in ATP to move compounds across membranes. Many ABC transporters are polyspecific and can transport a wide range of compounds. While this serves to protect our organs, for example, the brain, kidneys, and the placenta, it can also lead to the emergence of multidrug resistance in cancer cells, which can have devastating effects.
Despite their fundamental importance in health and disease, the mechanism of substrate translocation and recognition remains obscure. In the lab, we tackle this long-standing question using innovative approaches and careful structural interpretation to uncover the molecular mechanism of these marvelous nanomachines.
