Netherlands Bioinformatics Conference 2014

Netherlands Bioinformatics Conference 2014

Christian Ottmann

Christian Ottmann

CV

Dr. Christian Ottmann
Associate Professor (UHD)
Molecular Cell and Structural Biology
Chemical Biology
Dpt. of Biomedical Engineering
Technische Universiteit Eindhoven
P.O. Box 513
5600 MB EINDHOVEN
Tel. +31 40-247 2835

Christian Ottmann, Ph.D., is Associate Professor for Molecular Cell and Structural Biology at Eindhoven University of Technology, The Netherlands. He works on small-molecule modulation of Protein-Protein Interactions (PPIs) with a special focus on stabilization of 14-3-3 adapter protein PPIs. He is involved in several early drug discovery projects with the pharmaceutical industry and is coordinator of the FP7 Industry-Academia Partnership and Pathways (IAPP) 14-3-3STABS. Before taking up his current position in Eindhoven he was a group leader at the Chemical Genomics Centre (CGC) of the Max Planck Society in Dortmund, Germany. He obtained his Ph.D. (summa cum laude) in 2003 from the University of Tübingen with Prof. Claudia Oecking. In 2012 he was recipient of the Innovation Award in Medicinal/Pharmaceutical Chemistry of the GDCh/DPhG and in 2013 of the Young Chemical Biology Award of the International Chemical Biology Society (ICBS). He is (co-) author of more than 50 scientific papers and 3 patents.

Abstract

Title: Modulation of 14-3-3 Protein-Protein Interactions (PPIs) by small-molecules: new way of therapeutic intervention?

PDF file abstract

Targeted pharmacological modulation of Protein-Protein Interactions (PPIs) is a promising strategy in Chemical Biology and Drug Development. However, in the vast majority of cases this concept has been realized only for inhibition of PPIs despite the fact that in many biomedical contexts stabilization of PPIs would be desirable [1]. The natural product fusicoccin A is stabilizing the binding of 14-3-3 adapter proteins to the plant H+-ATPase PMA serving as proof-of-principle molecule for the possibility to address the widespread interactome of 14-3-3 proteins. In humans, these proteins interact with partner proteins implicated for example in cancer (p53, Raf, YAP/TAZ, β-catenin) or neurodegenerative diseases (Tau, α-Synuclein, LRRK2). We have devised a fusicoccin-derivative (FC-THF) that stabilizes the interaction of 14-3-3 with the K+ channel TASK-3 and have shown that a related natural product (Cotylenin A) stabilizes the inhibitory binding of 14-3-3 to C-Raf). Protein crystallography shows how these molecules bind to the rim of the interface of 14-3-3 proteins and partner protein-derived phosphopeptides contacting both protein partners simultaneously. Since binding of 14-3-3 proteins mediates trafficking of TASK-3 to the plasma membrane administration of FC-THF enhances surface expression of the channel in cells and increases K+ currents. Together with the demonstration that 14-3-3 PPI stabilizers can be identified by screening conventional compound libraries these studies support the concept of small-molecule PPI stabilization for biomedical research. In addition, we have also shown that inhibition of 14-3-3 PPIs is a feasible approach in certain physiological settings.



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