Fragment-Based Interrogation of the 14-3-3/TAZ Protein-Protein Interaction.
Blaž Andlovic, Dario Valenti, Federica Centorrino, Francesca Picarazzi, Stanimira Hristeva, Malgorzata Hiltmann, Alexander Wolf, François-Xavier Cantrelle, Mattia Mori, Isabelle Landrieu, Laura M Levy, Bert Klebl, Dimitrios Tzalis, Thorsten Genski, Jan Eickhoff, Christian Ottmann
Author Information
Blaž Andlovic: Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.
Dario Valenti: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
Federica Centorrino: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
Francesca Picarazzi: Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.
Jan Eickhoff: Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.
Christian Ottmann: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands. ORCID
The identification of chemical starting points for the development of molecular glues is challenging. Here, we employed fragment screening and identified an allosteric stabilizer of the complex between 14-3-3 and a TAZ-derived peptide. The fragment binds preferentially to the 14-3-3/TAZ peptide complex and shows moderate stabilization in differential scanning fluorimetry and microscale thermophoresis. The binding site of the fragment was predicted by molecular dynamics calculations to be distant from the 14-3-3/TAZ peptide interface, located between helices 8 and 9 of the 14-3-3 protein. This site was confirmed by nuclear magnetic resonance and X-ray protein crystallography, revealing the first example of an allosteric stabilizer for 14-3-3 protein-protein interactions.
