Tau proteins play an important role in the proper assembly and function of neurons. Hyperphosphorylation of tau by kinases such as tau tubulin kinase (TTBK) has been hypothesized to cause the aggregation of tau and the formation of neurofibrillary tangles (NFTs) that lead to the destabilization of microtubules, thereby contributing to neurodegenerative diseases such as Alzheimer's disease (AD). There are two TTBK isoforms with highly homologous catalytic sites but with distinct tissue distributions, tau phosphorylation patterns and loss‐of‐function effects. Inhibition of TTBK1 reduces the levels of NFT formation involved in neurodegenerative diseases such as AD, whereas inhibition of TTBK2 may lead to the movement disorder spinocerebellar ataxia type 11 (SCA11). Hence, it is critical to obtain isoform‐selective inhibitors. Structure‐based drug design (SBDD) has been used to design highly potent and exquisitely selective inhibitors. While structures of TTBK1 have been reported in the literature, TTBK2 has evaded structural characterization. Here, the first crystal structure of the TTBK2 kinase domain is described. Furthermore, the crystal structure of human TTBK2 in complex with a small‐molecule inhibitor has successfully been determined to elucidate the structural differences in protein conformations between the two TTBK isoforms that could aid in SBDD for the design of inhibitors that selectively target TTBK1 over TTBK2.

中文翻译：

---

与小分子抑制剂复合的tau微管蛋白激酶2催化结构域的晶体结构。

Tau蛋白在神经元的正确组装和功能中起重要作用。据推测，诸如tau微管蛋白激酶（TTBK）之类的激酶会使tau过度磷酸化，从而导致tau聚集并形成神经原纤维缠结（NFT），从而导致微管不稳定，从而导致神经退行性疾病，例如阿尔茨海默氏病（AD） ）。有两种TTBK亚型具有高度同源的催化位点，但具有不同的组织分布，tau磷酸化模式和功能丧失效应。抑制TTBK1可降低神经退行性疾病（如AD）中NFT形成的水平，而抑制TTBK2则可能导致运动性脊髓小脑共济失调11型（SCA11）。因此，获得同工型选择性抑制剂至关重要。基于结构的药物设计（SBDD）已用于设计高效且精制的选择性抑制剂。尽管在文献中已经报道了TTBK1的结构，但TTBK2避开了结构表征。在此，描述了TTBK2激酶结构域的第一晶体结构。此外，已经成功地确定了与小分子抑制剂复合的人TTBK2的晶体结构，以阐明两种TTBK同工型之间蛋白质构象的结构差异，这可以帮助SBDD设计选择性地靶向TTBK1而不是TTBK2的抑制剂。首先描述TTBK2激酶结构域的第一晶体结构。此外，已经成功地确定了与小分子抑制剂复合的人TTBK2的晶体结构，以阐明两种TTBK同工型之间蛋白质构象的结构差异，这可以帮助SBDD设计选择性地靶向TTBK1而不是TTBK2的抑制剂。首先描述TTBK2激酶结构域的第一晶体结构。此外，已经成功地确定了与小分子抑制剂复合的人TTBK2的晶体结构，以阐明两种TTBK同工型之间蛋白质构象的结构差异，这可以帮助SBDD设计选择性地靶向TTBK1而不是TTBK2的抑制剂。