Rational Design,Binding Studies,and Crystal‐Structure Evaluation of the First Ligand Targeting the Dimerization Interface of the 14‐3‐3ζ Adapter Protein |
| |
| Authors: | Dr. Martin Ehlers Jean‐Noël Grad Dr. Sumit Mittal David Bier Marcel Mertel Ludwig Ohl Dr. Maria Bartel Jeroen Briels Marius Heimann Prof. Dr. Christian Ottmann Prof. Dr. Elsa Sanchez‐Garcia Prof. Dr. Daniel Hoffmann Prof. Dr. Carsten Schmuck |
| |
| Affiliation: | 1. Institute of Organic Chemistry, University of Duisburg–Essen (Germany), Essen, Germany;2. Department of Bioinformatics and Computational Biophysics, ZMB/Faculty of Biology, University of Duisburg–Essen, Essen, Germany;3. Computational Biochemistry, University of Duisburg–Essen, Essen, Germany;4. Department of Chemistry, University of Duisburg–Essen, Essen, Germany;5. Department of Biomedical Engineering and, Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Eindhoven, Netherlands |
| |
| Abstract: | 14‐3‐3 Proteins play a central role in signalling pathways in cells: they interact as gatekeeper proteins with a huge number of binding partners. Their function as hub for intracellular communication can explain why these adapter proteins are associated with a wide range of diseases. How they control the various cellular mechanisms is still unclear, but it is assumed that the dimeric nature of the 14‐3‐3 proteins plays a key role in their activity. Here, we present, to the best of our knowledge, the first example of a small molecule binding to the 14‐3‐3ζ dimerisation interface. This compound was designed by rational in silico optimisation of a peptidic ligand identified from biochemical screening of a peptidic library, and the binding was characterised by UV/Vis spectroscopy, microscale thermophoresis, multiscale simulations, and X‐ray crystallography. |
| |
| Keywords: | molecular recognition protein binding protein– protein interactions molecular dynamics supramolecular chemistry |
|
|
