Development of the inhibitor for tangle formation of tau protein : Basic research for prevention of Altzheimer disease

(1)tau蛋白的微管结合结构域（MBD）是负责PHF形成的区域。我们成功地制备了选择性识别MBD的抗体Tau 2 r3。其可变区Fab 2 r3与MBD的VQIINK片段肽的复合物晶体的X射线晶体结构分析阐明了整个复合物结构。现在，我们正在研究MBD的抗体在原子水平上的识别模式。(2)本文采用~ 1H-NMR等物理化学方法研究了迄今为止发现的一系列抑制剂的MBD相互作用，明确了表现抑制活性所必需的结构要素，即结构单元。例如，抑制剂具有在环上包括极性原子（O或N）或极性基团（NH或OH）的平面芳族环。另一方面，一系列tau突变体的PHF形成实验阐明了MBD第三重复序列中Ile 308和Tyr 310残基之间的CH. π相互作用的重要性。

(1) The microtubule-binding domain (MBD) of tau protein is the region responsible for the PHF formation. We succeed in the preparation of an antibody Tau2r3, which selectively recognizes the MBD. The X-ray crystal structure analysis of the complex crystal of its variable region, Fab2r3, with the VQIINK fragment peptide of MBD clarified the overall complex structure. Now, we are investigating the recognition mode of MBD by the antibody at the atomic level. (2) The MBD interaction of a series of inhibitors we discovered so far were investigated by 1H-NMR and other physicochemical methods, and clarified the structural elements necessary for exhibiting the inhibitory activity, i. e., inhibitor has a planar aromatic ring including the polar atom (O or N) or polar group (NH or OH) on the ring. On the other hand, the PHF formation experiment of a series of tau mutants clarified the important of CH…π interaction between Ile308 and Tyr310 residues in the third repeat of MBD.