The Crystal Structure of the Green Tea Polyphenol (-)-Epigallocatechin Gallate-Transthyretin Complex Reveals a Novel Binding Site Distinct from the Thyroxine Binding Site
The Crystal Structure of the Green Tea Polyphenol (-)-Epigallocatechin Gallate-Transthyretin Complex Reveals a Novel Binding Site Distinct from the Thyroxine Binding Site
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DOI：
10.1021/bi1004409
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发表时间：
2010-07-27
期刊：
影响因子：
2.9
通讯作者：
Kai, Hirofumi
中科院分区：
文献类型：
--
作者：
Miyata, Masanori;Sato, Takashi;Kai, Hirofumi
淀粉样原纤维形成与蛋白质错误折叠病症相关，包括神经退行性疾病如阿尔茨海默病、帕金森病和亨廷顿病。家族性淀粉样多发性神经病（FAP）是一种遗传性疾病，由结合并转运甲状腺素（T（4））的人血浆蛋白甲状腺素运载蛋白（TTR）的点突变引起。TTR变体通过在细胞外环境中形成淀粉样纤维而促成淀粉样变性的发病机制。最近的报道显示，表没食子儿茶素3-没食子酸酯（EGCG），绿色茶的主要多酚成分，结合TTR并抑制TTR淀粉样纤维形成。然而，尚未进行EGCG与TTR结合的结构分析。在这里，我们首先研究了EGCG-V30 M TTR复合物的晶体结构，并发现了与甲状腺素结合位点不同的新结合位点，这表明EGCG具有与先前显示结合和稳定TTR四聚体结构的化合物不同的作用模式。此外，表没食子儿茶素没食子酸酯在临床报道的TTR变体的细胞系统中诱导寡聚化和单体抑制。总之，这些发现表明，EGCG可能是FAP治疗的候选化合物。
Amyloid fibril formation is associated with protein misfolding disorders, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Familial amyloid polyneuropathy (FAP) is a hereditary disease caused by a point mutation of the human plasma protein, transthyretin (TTR), which binds and transports thyroxine (T(4)). TTR variants contribute to the pathogenesis of amyloidosis by forming amyloid fibrils in the extracellular environment. A recent report showed that epigallocatechin 3-gallate (EGCG), the major polyphenol component of green tea, binds to TTR and suppresses TTR amyloid fibril formation. However, structural analysis of EGCG binding to TTR has not yet been conducted. Here we first investigated the crystal structure of the EGCG-V30M TTR complex and found novel binding sites distinct from the thyroxine binding site, suggesting that EGCG has a mode of action different from those of previous chemical compounds that were shown to bind and stabilize the TTR tetramer structure. Furthermore, EGCG induced the oligomerization and monomer suppression in the cellular system of clinically reported TTR variants. Taken together, these findings suggest the possibility that EGCG may be a candidate compound for FAP therapy.