4Y32

Crystal structure of C-terminal modified Tau peptide-hybrid 109B with 14-3-3sigma

4Y32 の概要

• エントリーDOI: 10.2210/pdb4y32/pdb
• 関連するPDBエントリー: 4FL5 4Y3B 4Y3V 4Y5I
• 分子名称: 14-3-3 protein sigma, ARG-THR-PRO-SEP-LEU-PRO-CNC(C(C)O)C(=O)N1CCCC1CCOC, (2S)-2-(2-methoxyethyl)pyrrolidine, ... (4 entities in total)
• 機能のキーワード: peptide-hybrid, inhibitor, protein-protein interaction, peptide binding protein, adapter protein, 14-3-3, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 54918.75

構造登録者

Bartel, M.,Milroy, L.,Bier, D.,Brunsveld, L.,Ottmann, C. (登録日: 2015-02-10, 公開日: 2015-12-23, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)