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).

Curriculum Vitae

Professional career

Scientific education and degrees

Selected Publications

E. Sijbesma , E. Visser , K. Plitzko, P. Thiel, L.-G. Milroy, M. Kaiser, L. Brunsveld, C. Ottmann: Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein-protein interactions. Nat Commun. 2020 Aug 7;11(1): 3954.doi: 10.1038/s41467-020-17741-0.

C. Ottmann: A Supramolecular Stabilizer of the 14-3-3ζ/ERα Protein-Protein Interaction with a Synergistic Mode of Action. Angew Chem Int Ed Engl. 2019 Dec 9. doi: 10.1002/anie.201914517.

A. Kuusk, J. F. Neves, K. Bravo Rodriguez, A. Gunnarsson, Y. B. Ruiz-Blanco, M. Ehrmann, H. Chen, I. Landrieu, E. Sanchez-Garcia , H. Boyd, C. Ottmann, R. G. Doveston: Adoption of a Turn Conformation Drives the Binding Affinity of p53 C-Terminal Domain Peptides to 14-3-3σ. ACS Chem. Biol. 2019 Nov doi 10.1021/acschembio.9b00893.

D. Bier, S. Mittal, K. Bravo-Rodriguez, A. Sowislok, X. Guillory, J. Briels, C. Heid, M. Bartel, B. Wettig, L. Brunsveld, E. Sanchez-Garcia , T. Schrader, C. Ottmann: The Molecular Tweezer CLR01 Stabilizes a Disordered Protein-Protein Interface. J Am Chem Soc. 2017 Nov 15;139(45):16256-16263. doi: 10.1021/jacs.7b07939. Epub 2017 Nov 2.

P. de Vink, J. Briels, T. Schrader, L. Milroy, L. Brunsveld, C. Ottmann: Cucurbit[8]uril and 14-3-3 based binary bivalent supramolecular-protein assembly platform and co-crystal structure. Angew Chem Int Ed Engl. 2017 May 16. doi: 10.1002/anie.201701807

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.