Connecting membrane binding to function or misfunction. Generating selectivity in cellular applications. How do hormones talk to their receptors? Improving NMR efficiency and applicability. What is the most suitable membrane mimetic for a given question?

Research

Most biological processes are driven by (inter)actions of proteins, nucleic acids or lipids. The diverse functions are in general associated with the three-dimensional structure and dynamics of the respective molecules. We are interested in understanding the structural features of life's key players and to use our insights to identify new therapeutic opportunities to interfere with disease-related processes. In this respect we focus on:

Membrane systems in neuronal signalling:

Membranes act as the central interface between environment and cellular response. As such membrane proteins are the most frequent targets of modern drugs. In addition, also the lipids themselves can directly modulate biological processes. We investigate the molecular mechanisms underlaying central neuronal communication pathways. The key players in this interaction network are (i) membrane protein receptors (GPCRs), (ii) neuropeptides, and (iii) lipid-membranes. We are in particular interested in deciphering:

For high-resolution insights we predominantly make use of the power of NMR spectroscopy including its wide range of useful sub techniques. However, to reliably answer the above questions, integrative approaches that combine most suitable biophysical and biochemical techniques are required. Using a combination of solution- and solid-state NMR, fluorescence- and surface-based techniques, as well as molecular dynamic simulations, we recently could e.g. connect membrane binding modes with aggregation of the protein alpha synuclein, a process linked to Parkinson's disease.
- see e.g. Viennet et al. Commun Biol. 2018, and Falke et al. Chem Phys Lip 2019, for more details.

NMR method development:

While NMR has the potential to obtain atomic-resolution insights into native biological systems, most NMR methods face increasing limitations when sample complexity is approaching native conditions. Our NMR method development therefore aims to provide improvements that are in particular useful for challenging biological systems. Our recently developed UTOPIA NMR setup allows e.g. the acquisition of relaxation favorable 13C and 15N spectra during the acquisition of the conventional 1H detected spectra. The additional spectra can be obtained for free and contain otherwise not accessible information.
- see e.g. Viegas et al. JbNMR 2016, for more details.

Experiments to share
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In general, NMR is also applicable directly in cellular environments. However, cellular NMR's limitations comprise mainly signal sensitivity as well as selectively of the protein of interest. Combining the sensitivity boost of dynamic nuclear polarization (DNP) with the selectivity of protein interactions, both limitations can be reduced enabling the investigation of a target protein in a cellular context.
- see e.g. Viennet et al. Angew Chem 2016, for more details.



Biocatalysis:

Catalytic function in biological systems is usually carried out by proteins (enzymes) as well as catalytically active RNAs (ribozymes). So far, no catalytic DNA has been found in nature. However, several different catalytically active DNA sequences have been identified by in vitro selection and been named DNAzymes. We aim to obtain a comprehensive mechanistic understanding of DNA-mediated catalysis to unravel the enormous potential of this process for therapeutic applications.
Experiments to share