Laboratory of Chemical Biology and Institute of Complex Molecular Systems (ICMS), Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven (The Netherlands).
UMR 8576 CNRS-Lille University, 59000 Villeneuve O'Ascq (France).
Angew Chem Int Ed Engl. 2015 Dec 21;54(52):15720-4. doi: 10.1002/anie.201507976. Epub 2015 Nov 5.
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.
新型蛋白-蛋白相互作用（PPI）调节剂的发现是现代分子挑战之一。PPIs 可以通过抑制剂或稳定剂化合物来调节，这些化合物针对蛋白质界面的不同但接近的区域。原则上，蛋白质稳定剂复合物可以指导 PPI 抑制剂的设计（反之亦然）。在本工作中，我们结合了衔接蛋白 14-3-3 的稳定剂和抑制剂共晶复合物的 X 射线晶体学数据，从原子尺度上描述了 14-3-3/Tau PPI 的抑制剂，这是一种治疗阿尔茨海默病的潜在药物靶点。根据 NMR 光谱研究，最有效的化合物显著抑制了磷酸化全长 Tau 与 14-3-3 的结合。我们的工作为通过 PPI 稳定剂-蛋白质复合物指导的 PPI 抑制剂的合理设计奠定了基础，同时可能使人们能够获得 14-3-3 和其他 PPI 的新的合成上可处理的稳定剂。
