Fragment-Based Interrogation of the 14–3–3/TAZ Protein–Protein Interaction

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.

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Publication Details

Journal
Biochemistry
Published
2024-08-22
DOI
https://doi.org/10.1021/acs.biochem.4c00248
Citations
10
Primary Topic
14-3-3 protein interactions
Type
article
Field-Weighted Citation Impact
2.34

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article

Fragment-Based Interrogation of the 14–3–3/TAZ Protein–Protein Interaction

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10 citations
Biochemistry
14-3-3 protein interactions
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article

Fragment-Based Interrogation of the 14–3–3/TAZ Protein–Protein Interaction

Dimitrios Tzalis, Bert Klebl, Christian Ottmann, Francesca Picarazzi, Isabelle Landrieu, Jan Eickhoff, Dario Valenti, Laura M. Levy, Thorsten Genski, François‐Xavier Cantrelle, Stanimira Hristeva, Blaž Andlovic, Mattia Mori, Federica Centorrino, Alexander Wolf, Malgorzata Hiltmann
article en
10 citations

Abstract

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.

BiochemistryVol. 63(17)
University of Siena (IT), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Lille (FR), Institut Pasteur de Lille (FR), Lead Discovery Center (Germany) (DE), Eindhoven University of Technology (NL)
Università degli Studi di Siena, Université de Lille, Institut National de la Santé et de la Recherche Médicale, Technische Universiteit Eindhoven, Centre National de la Recherche Scientifique, H2020 Marie Skłodowska-Curie Actions
Openalex Percentile: Top 11%
14-3-3 protein interactions
2.34
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