4Y32: Crystal Structure Of C-terminal Modified Tau Peptide-hybrid 109b With 14-3-3sigma

Citation:
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.
PDB ID: 4Y32Download
MMDB ID: 134998
PDB Deposition Date: 2015/2/10
Updated in MMDB: 2015/12
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4Y32: tetrameric; determined by software (PISA)
Molecular Components in 4Y32
Label Count Molecule
Proteins (4 molecules)
2
14-3-3 Protein Sigma(Gene symbol: SFN)
Molecule annotation
2
Arg-thr-pro-sep-leu-pro-cnc(c(c)o)c(=o)n1cccc1ccoc
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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