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首页> 外文期刊>Biochemistry >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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The Crystal Structure of the Green Tea Polyphenol (-)-Epigallocatechin Gallate-Transthyretin Complex Reveals a Novel Binding Site Distinct from the Thyroxine Binding Site

机译：绿茶多酚（-）-表没食子儿茶素没食子酸酯-运甲状腺素蛋白复合物的晶体结构揭示了与甲状腺素结合位点不同的新型结合位点

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摘要

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.
机译：淀粉样蛋白原纤维形成与蛋白质错误折叠疾病有关，包括神经退行性疾病，例如阿尔茨海默氏病，帕金森氏病和亨廷顿氏病。家族性淀粉样蛋白多神经病（FAP）是一种遗传性疾病，由人血浆蛋白运甲状腺素蛋白（TTR）的点突变引起，该蛋白结合并转运甲状腺素（T-4）。 TTR变体通过在细胞外环境中形成淀粉样蛋白原纤维来促进淀粉样变性病的发病机理。最近的一份报告显示，绿茶中的主要多酚成分表没食子儿茶素3-没食子酸酯（EGCG）与TTR结合并抑制TTR淀粉样蛋白原纤维的形成。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-V30M TTR复合物的晶体结构，发现了不同于甲状腺素结合位点的新结合位点，这表明EGCG的作用方式不同于已显示出结合并稳定TTR的先前化合物。四聚体结构。此外，EGCG诱导了临床报道的TTR变异体在细胞系统中的低聚和单体抑制作用。综上所述，这些发现表明，EGCG可能是FAP治疗的候选化合物。

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