CRC 1093 - Principal Investigator Christian Ottmann

Dr. Christian Ottmann

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Phone: +31 40-247 2835
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Department of Biomedical Engeneering

Technical University Eindhoven

Faculty of Chemistry

University of Duisburg-Essen

Area B: Biological Targets B4: Modulation of 14-3-3 protein-protein interactions by supramolecular chemistry

Project B4 will mechanistically and structurally characterize the effect of molecular tweezers and combinatorial ligands on various 14-3-3 proteins with a particular focus on prominent 14-3-3 targets such as Raf kinases, p53 and aminopeptidase N (CD13). Protein crystallography in tandem with biophysical methods like SPR, thermophoresis and ITC will be employed to draw an exact picture of the mechanistic basis of these modulations, which will be further refined by MD simulations and QM/MM calculations. The most potent binders will be used to modulate the extracellular 14-3-3 protein-protein interactions with aminopeptidase N (CD13).

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Curriculum Vitae

Professional career

Scientific education and degrees

 

Selected Publications

L. M. Stevers, C. V. Lam, S. F.Leysen, F. A. Meijer, D. S. van Scheppingen, R. M. de Vries, G. W. Carlile, L. G. Milroy, D. Y. Thomas, L. Brunsveld, C. Ottmann: Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR. Proc Natl Acad Sci U S A. 2016 Mar 1; 113(9):E1152-61.

L. G. Milroy, M. Bartel, M. A. Henen, S. Leysen, J. M. Adriaans, L. Brunsveld, I. Landrieu, C. Ottmann: Stabilizer-Guided Inhibition of Protein-Protein Interactions. Angew. Chem. Int. Ed. 2015, 54, 15720-4.

L. G. Milroy, T. N. Grossmann, S. Hennig, L. Brunsveld, C. Ottmann: Modulators of protein-protein interactions. Chemical Reviews 2014, 114, 4695-748.

A. Glas, D. Bier, G. Hahne, C. Rademacher, C. Ottmann, T. N. Grossmann: Constrained Peptides with Target-Adapted Cross-Links as Inhibitors of a Pathogenic Protein-Protein Interaction. Angew. Chem. Int. Ed. 2014, 53, 2489-93.

M. Skwarczynska, M. Molzan, C. Ottmann: Activation of NF-κB signalling by fusicoccin-induced dimerization. Proc. Natl. Acad. Sci. USA. 2013, 110, E377-86.

D. Bier, R. Rose, K. Bravo-Rodriguez, M. Bartel, J. M. Ramirez-Anguita, S. Dutt, C. Wilch, F. G. Klärner, E. Sanchez-Garcia, T. Schrader, C. Ottmann: Molecular tweezers modulate 14-3-3 protein-protein interactions. Nat. Chem. 2013, 5, 234-9.

P. Thiel, R. Röglin, N. Meissner, S. Hennig, O. Kohlbacher, C. Ottmann: Virtual Screening and Experimental Validation Reveal Novel Small-Molecule Inhibitors of 14-3-3 Protein-Protein Interactions. Chem. Commun. 2013, 49, 8468-70.

M. Molzan, S. Kasper, L. Röglin, M. Skwarczynska, T. Sassa, T. Inoue, F. Breitenbuecher, J. Ohkanda, N. Kato, M. Schuler, C. Ottmann: Stabilization of Physical RAF/14-3-3 Interaction by Cotylenin A as Treatment Strategy for RAS Mutant Cancers. ACS Chem Biol. 2013, 8, 1869-75.

R. Rose, S. Erdmann, S. Bovens, A. Wolf, M. Rose, S. Hennig, H. Waldmann, C. Ottmann:  Identification of small molecule stabilizers of 14-3-3 protein-protein interactions.  Angew. Chem. Int. Ed. 2010. 49, 4129-4132.

C. Ottmann, S. Marco, N. Jaspert, C. Marcon, N. Schauer, M. Weyand, C. Vandermeeren, G. Duby, M. Boutry, A. Wittinghofer, J. L. Rigaud, C. Oecking: Structure of a 14-3-3 coordinated hexamer of the plant plasma membrane H+-ATPase by combining x-ray crystallography and electron cryomicroscopy.  Mol. Cell. 2007, 25, 427-440.