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

被引：2

作者：

Andlovic, Blaz ^{[1
,2
,3
]}

Valenti, Dario ^{[2
,3
,4
]}

Centorrino, Federica ^{[2
,3
]}

Picarazzi, Francesca ^{[5
]}

Hristeva, Stanimira ^{[4
]}

Hiltmann, Malgorzata ^{[1
]}

Wolf, Alexander ^{[1
]}

Cantrelle, Francois-Xavier ^{[6
,7
]}

Mori, Mattia ^{[5
]}

Landrieu, Isabelle ^{[6
,7
]}

Levy, Laura M. ^{[4
]}

Klebl, Bert ^{[1
]}

Tzalis, Dimitrios ^{[4
]}

Genski, Thorsten ^{[4
]}

Eickhoff, Jan ^{[1
]}

Ottmann, Christian ^{[2
,3
]}

机构：

[1] Lead Discovery Ctr GmbH, D-44227 Dortmund, Germany

[2] Eindhoven Univ Technol, Dept Biomed Engn, Lab Chem Biol, NL-5612 AZ Eindhoven, Netherlands

[3] Eindhoven Univ Technol, Inst Complex Mol Syst, NL-5612 AZ Eindhoven, Netherlands

[4] Taros Chem GmbH & Co KG, D-44227 Dortmund, Germany

[5] Univ Siena, Dept Biotechnol Chem & Pharm, I-53100 Siena, Italy

[6] Univ Lille, CNRS EMR9002, Integrat Struct Biol, F-59000 Lille, France

[7] Univ Lille, Inst Pasteur Lille, INSERM, RID AGE Risk Factors & Mol Determinants Aging Rela, F-59000 Lille, France

来源：

BIOCHEMISTRY | 2024年 / 63卷 / 17期

基金：

欧盟地平线“2020”;

关键词：

SMALL-MOLECULE STABILIZATION; LIGAND-BINDING; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; HIPPO PATHWAY; DISCOVERY; PHOSPHORYLATION; INHIBITOR; RECEPTOR; TARGETS;

D O I：

10.1021/acs.biochem.4c00248

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2196 / 2206

页数：11

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