The research in the department of Biochemistry concentrates on biochemical and structural studies on proteins derived from pathogens and their host cells to understand molecular mechanisms that are essential for various steps of the replication cycle. A second focus is the development of novel protein crystallization and diffraction data collection strategies.
Our major goals are:

  1. Structural characterization of virus glycoproteins and their interactions with the immune system together with the identification of the determinants of an efficient neutralizing antibody response to facilitate informed vaccine design. During the last years we have put forward the hypothesis - now widely accepted in the field - that the receptor binding site within the hepatitis C virus (HCV) glycoproteins - representing the major target of neutralizing antibodies - is conformationally flexible. This conformational flexibility likely constitutes a novel strategy that HCV utilizes to evade potently neutralizing antibodies and is therefore directly relevant for vaccine design.
  2. Understanding the principles that underlie intracellular protein crystallization and exploit this native capability of cells for X-ray crystallography to offer a versatile alternative to “in-surfo” crystallization. To this end we have established a platform for intracellular crystallization of recombinant proteins in insect cells.
  3. We have established a pipeline to identify and characterize monoclonal human antibodies that potently neutralize a number of different viruses using advanced single cell technology combined with Next Generation Sequencing, recombinant protein expression, structure determination using X-ray crystallography and biochemical characterization of antibody-antigen interaction. We have recently used this platform to isolate human neutralizing antibodies that efficiently act against the majority of currently circulating SARS-CoV-2 variants.
  4. Understanding the effect of viral protein modifiers, specifically SUMO and ubiquitin ligases from different herpesviruses. Changing the SUMOylation status of cellular proteins is often beneficial for viral infection and may enable the switch from latent to lytic life cycles inherent to herpesviruses. To understand the details of these interactions, we use biochemical and biophysical methods and structural biology with viral and cellular multi-protein complexes.
  5. The genome size of RNA viruses is usually restricted by the low fidelity of the RNA synthesis process. Interestingly, members of the order Nidovirales feature large RNA genomes that suggest a proof-reading activity by a 3’-5’ exoribonuclease (ExoN). We aim to structurally and functionally characterize ExoN proteins from different Nidovirus subfamilies such as Coronaviridae and Tobaniviridae to gain detailed insights into the role that ExoN plays in viral RNA replication fidelity.
  6. Understanding the mechanism-of-action leading to the assembly and disassembly of large viral capsids, an essential step for the production of virus progeny as well as for the release of the viral genome during virus entry. Our recent crystal structures of herpesvirus capsid proteins have revealed an “achilles heel” that could be explored to develop urgently needed novel antiviral therapies.
  7. We develop and optimize serial diffraction data collection strategies at synchrotron sources and X-ray free-electron lasers.

In general, we study mostly pathogens that constitute a global public health and/or veterinary concern and use structural biology/biophysical methods with a special focus on X-ray crystallography. The structural knowledge gained from our experiments can be used for structure-based design of preventive or curative anti-infective agents, i.e., this knowledge has a direct potential for translational medicine. Furthermore, structural studies are often performed in parallel on homologous proteins from related pathogens, which provides crucial information about the evolutionary relationship between them and allows the identification of conserved features and/or pathways, which often are the most promising drug targets.