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

Autor:	Andlovic B; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany.; 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., Valenti D; 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.; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227 Dortmund, Germany., Centorrino F; 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., Picarazzi F; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy., Hristeva S; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227 Dortmund, Germany., Hiltmann M; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Wolf A; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Cantrelle FX; CNRS EMR9002 Integrative Structural Biology, University of Lille, F-59000 Lille, France.; University of Lille, Inserm, Institut Pasteur de Lille, U1167─RID-AGE─Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000 Lille, France., Mori M; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy., Landrieu I; CNRS EMR9002 Integrative Structural Biology, University of Lille, F-59000 Lille, France.; University of Lille, Inserm, Institut Pasteur de Lille, U1167─RID-AGE─Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000 Lille, France., Levy LM; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227 Dortmund, Germany., Klebl B; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Tzalis D; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227 Dortmund, Germany., Genski T; Taros Chemicals GmbH & Co. KG, Emil-Figge-Straße 76a, 44227 Dortmund, Germany., Eickhoff J; Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany., Ottmann C; 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.
Jazyk:	angličtina
Zdroj:	Biochemistry [Biochemistry] 2024 Sep 03; Vol. 63 (17), pp. 2196-2206. Date of Electronic Publication: 2024 Aug 22.
DOI:	10.1021/acs.biochem.4c00248
Abstrakt:	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.
Databáze:	MEDLINE
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