Research

We are fascinated by Proteins. They are the workhorses in almost all cellular processes and come with an amazing diversity of functions and interactions. To manage their daily tasks and social behavior, they must be able to interact properly with their environment. Proteins must specifically recognize other biomolecules, which may be substrates for catalysis or partner proteins to form larger macromolecular complexes. We seek to understand the architecture, mechanisms and evolution of macromolecular complexes and machines, by combining methods of structural biology with computational approaches and biochemical assay development. We have a strong focus on molecular recognition processes and exploit our findings for drug development in collaboration with medicinal chemists.

Investigational approaches

We generally rely on the integration of complementary methods to obtain insight into dynamics and to overcome technical artifacts of individual methods. For structural characterization, we routinely employ X-ray crystallography, electron microscopy, small angle scattering, and - in collaboration - NMR spectroscopy, which we complement with computational approaches. For drug development, we dissect the structure-activity relationship of small molecules using X-ray crystallography/NMR and develop bespoken biophysical assays.

Integrative Structural Biology of Macromolecular Systems

We study the spatial organization, functional dynamics, and evolutionary driving forces of biomolecular interactions in metabolic pathways and macromolecular complexes. We integrate structural data with biochemical, biophysical and computational approaches to decipher the architectural principles and the dynamics, the functioning, and possible catalytic advantages of these assemblies. One example of this research is the characterization of the AROM complex, an assembly of ten enzymatic domains catalyzing the five central steps of the shikimate pathway in fungi. Another example is the ubiquitin-proteasome system (UPS), a key system for therapeutic intervention.

Targeted protein degradation

In targeted protein degradation, E3 ubiquitin ligases of the UPS are repurposed to degrade proteins for a specific therapeutic need. The human genome encodes for several hundred such ligases, which are specialized in their substrate recognition and spatiotemporal expression. So far, only a small fraction of those have been unlocked for targeted protein degradation. For their repurposing, "degrader" molecules are designed, which can be based on either small molecules or on peptides. In practice, these approaches are limited by the number of currently available E3 ligases and ligands, and we are addressing this limitation in our research: We are probing the chemical ligand space of E3-ligase substrate receptors to develop functional therapeutic degraders in collaboration with medicinal chemists.