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

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.

SUBMITTER: Andlovic B

PROVIDER: S-EPMC11375770 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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

Andlovic Blaž B Valenti Dario D Centorrino Federica F Picarazzi Francesca F Hristeva Stanimira S Hiltmann Malgorzata M Wolf Alexander A Cantrelle François-Xavier FX Mori Mattia M Landrieu Isabelle I Levy Laura M LM Klebl Bert B Tzalis Dimitrios D Genski Thorsten T Eickhoff Jan J Ottmann Christian C

Biochemistry 20240822 17

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 ...[more]

PMID: 39172504

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