4Y5I

Crystal structure of C-terminal modified Tau peptide-hybrid 126B with 14-3-3sigma

Summary for 4Y5I

• Entry DOI: 10.2210/pdb4y5i/pdb
• Related: 4Y32 4Y3B 4Y3V
• Descriptor: 14-3-3 protein sigma, Microtubule-associated protein tau, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: 14-3-3 sigma, protein-protein interaction, inhibitor, tau, peptide-hybrid, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 55046.80

Authors

Leysen, S.,Bartel, M.,Milroy, L.,Brunsveld, L.,Ottmann, C. (deposition date: 2015-02-11, release date: 2016-01-13, Last modification date: 2024-11-20)

Primary citation

Milroy, L.G.,Bartel, M.,Henen, M.A.,Leysen, S.,Adriaans, J.M.,Brunsveld, L.,Landrieu, I.,Ottmann, C.
Stabilizer-Guided Inhibition of Protein-Protein Interactions.
Angew.Chem.Int.Ed.Engl., 54:15720-15724, 2015

PubMed Abstract: 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 X-ray crystallographic data from both stabilizer and inhibitor co-crystal 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.

PubMed: 26537010
DOI: 10.1002/anie.201507976

Experimental method

X-RAY DIFFRACTION (1.4 Å)