期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 54, 期 52, 页码 15720-15724出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201507976
关键词
drug discovery; peptide inhibitors; protein-protein interactions; structure-guided design
资金
- Netherlands Organization for Scientific Research [024.001.035]
- Marie Curie Action [PIAPP-GA-2011-286418 14-3-3Stabs]
- LabEx (Laboratory of Excellence) DISTALZ program (ANR) [ANR-11-LABX-009]
- North of France Region
- CNRS
- Pasteur Institute of Lille
- European Community through FEDER
- French Research Ministry
- Lille University
- TGE RMN THC, France [FR-3050]
The discovery of novel protein-protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein-stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine Xray crystallographic data from both stabilizer and inhibitor cocrystal complexes of the adapter protein 14-3-3 to characterize, down to the atomic scale, inhibitors of the 14-3-3/Tau PPI, a potential drug target to treat Alzheimer's disease. The most potent compound notably inhibited the binding of phosphorylated full-length Tau to 14-3-3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer-protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14-3-3 and other PPIs.
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