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Matthias Preller

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Bioinformatics

"CSSB provides a unique opportunity to collaborate directly with other scientists towards a common goal . Here I have a chance to study the structure and dynamics of biological macromolecules and develop a means to interfere with their function in a controlled manner."

Matthias Preller, CSSB Group-Leader

Previous and current research

De Novo Development of Novel Inhibitors of the Apicomplexan Parasite Invasion
Malaria is one of the most lethal tropical diseases caused by apicomplexan parasites. The Preller group applies a rational, structure-based approach to develop and analyse novel small molecule inhibitors, targeting the motility and invasion machinery of the parasites – the glideosome. Using a combination of computer-chemical predictions, organic synthesis as well as biophysical and structural analyses, we are designing, stereoselectively and biomimetically producing and mechanistically investigating small molecule glideosome inhibitors, which show inhibitory potencies against the blood and liver stages of the parasites. These compounds will be used as tools in biochemical and cell biological studies to understand the host cell invasion process of the parasites.

Molecular Mechanisms of Chemomechanical Coupling in the Motorprotein Myosin
The acto-myosin system constitutes the functional, contractile unit of the sarcomere in muscle cells. Acto-myosin motor activity is, however, not restricted to muscle cells. Mechanical work and directed movement is generated during the myosin power stroke – the key event of acto-myosin motor activity. However, our knowledge about the molecular events of chemomechanical coupling remains incomplete. The lack of structural information of important conformational states, as well as an insufficient description of the allosteric communication pathways within the motor domain has thus far prevented a full description of the mechanotransduction mechanism in molecular detail. We are using a multidisciplinary approach including state-of-the-art biophysical methods, crystallographic analysis and mechanistic simulations to shed light on the allosteric communication pathways within the motor protein that dictate the propagation of chemomechanical coupling signals leading to force production and movement.

Dynamics and Mechanisms of Disease-associated Mutations in Proteins
We are interested in understanding the consequences and molecular mechanisms underlying disturbances of the native function of protein systems by single point mutations.

Recently, we were able to elucidate the mechanisms of two mutations in cytoplasmic β-actin, which are related to severe human developmental malformations and deafness, on the structure, function, and dynamics of the molecules (Hundt et al., 2014) as well as the disturbing effect of point mutations in human connexin46 on the proper formation of gap junction channels in the human lens, leading to cataract (Schadzek et al., 2016).

Future Goals
Understanding the molecular mechanisms of mechanotransduction in motor proteins, in particular in the context of the apicomplexan glideosome, is of major interest to our research. Using this information will support the rational development of specific inhibitors of parasitic movement and host cell invasion processes and help us to improve our development strategy.

Publications

Roberts S., et al. (2018) Calcium Sensor for Photoacoustic Imaging. J Am Chem Soc; 40(8):2718-2721

Chinthalapudi K., et al. (2017) Mechanistic insights into the active site and allosteric communication pathways in human nonmuscle myosin-2C. Elife; 6

Mohammadi-Ostad-Kalayeh S., et al. (2017) Development of a microarray-based assay for efficient testing of new HSP70/DnaK inhibitors. Bioorg Med Chem; 25(24):6345-6352

Beyer U., et al. (2017) Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis. Acta Neuropathol; 134(6):905-922

Osmanovic A., et al. (2017) FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study. Eur J Hum Genet; 25(3):324-331

Schuster-Gossler K., et al. (2016) Context-Dependent Sensitivity to Mutations Disrupting the Structural Integrity of Individual EGF Repeats in the Mouse Notch Ligand DLL1. Genetics; 202(3):1119-33

Schadzek P., et al. (2016) Data of the molecular dynamics simulations of mutations in the human connexin46 docking interface. Data Brief; 7:93-9

Schadzek P., et al. (2016) The cataract related mutation N188T in human connexin46 (hCx46) revealed a critical role for residue N188 in the docking process of gap junction channels. Biochim. Biophys. Acta; 1858, 57-66
      
Radke M.B., et al. (2014) Small molecule-mediated refolding and activation of myosin motor function. Elife 3; e01603

Chaturvedi A., et al. (2013) Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 122; 2877-2887
      
Preller M., et al. (2013) The myosin start-of-power stroke state and how actin binding drives the power stroke. Cytoskeleton (Hoboken) 70; 651-660

Preller M., et al. (2011) Inhibition of Myosin ATPase activity by halogenated pseudilins: a structure-activity study. J. Med. Chem; 54, 3675-3685

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