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Structure of molecular factories and regulatory complexes

Hybrid methods approaches provide fundamental insights into metabolic regulation and new perspectives for drug discovery.

Metabolism summarizes all processes of biosynthesis and degradation of cellular building blocks. The necessary chemical conversions are catalyzed by a large number of specific enzymes. Regulatory protein complexes tightly control the activity of key metabolic enzymes in response to environmental or cellular conditions. Abnormal function or regulation of metabolism are the cause of several diseases. Dysregulation of lipid metabolism, for example, is linked to the development of cancer and is a risk factor for cardiovascular diseases and diabetes.

Multienzymes and large regulatory assemblies
Our research focuses on the architecture and functional principles of multienzymes and regulatory protein complexes. Multienzymes integrate several catalytic activities into single enzymes and form huge biological factories. They are involved in central steps of metabolism, for example the lipid biosynthesis, but are also key players in microbial production of bioactive drug candidates. Large regulatory assemblies, such as the target-of-rapamycin (TOR) complex, integrate hormonal and nutrient signals for a tight control of cellular growth and proliferation.

Hybrid methods: approach to study protein function
We combine experimental methods for high resolution structure analysis such as cryo electron microscopy and X-ray crystallography with computational technologies, advanced microscopy, and solution studies of molecular dynamics in ensemble mode and at single-molecule level. This hybrid structural biology approach enables us to comprehensively study the organization and dynamics of large macromolecular assemblies as well as their interplay with the cellular environment.

Basis for therapeutic interventions
A fundamental understanding of metabolism and metabolic regulation is crucial for a targeted therapeutic intervention. The TOR complex and lipid biosynthesis multienzymes are important targets for fighting cancer. Structural studies provide general insights into the function of these proteins and directly highlight opportunities for drug discovery.