EGCG, the most abundant favanol in green tea, is one of the few natural compounds known to inhibit amyloid fibril formation of proteins associated with neurodegeneration, and to disaggregate amyloid fibrils. Little is known of the mechanism of molecular action of EGCG, or how it or other small molecules interact with amyloid fibrils. Here we present a 3.9 angstrom resolution cryoEM structure that reveals the site of EGCG binding to AD brain-derived tau fibrils. The structure suggests that EGCG disaggregates fibrils of AD-tau by wedging into a cleft that is at the interface of two protofilaments of the paired helical filament, and by causing charge repulsions between tau layers of the fibril. In support of this, we observe separation of the protofilaments that EGCG wedges between, and accompanying displacement of the adjacent beta-helix domain. By resolving the site of EGCG binding, our structure defines a pharmacophore-like cleft in the AD-tau fibril that will be of use for the discovery of surrogate compounds with more desirable drug-like properties.

中文翻译：

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CryoEM揭示了小分子EGCG如何与AD脑源性tau纤维结合并引发纤维分解

EGCG是绿茶中含量最高的黄烷醇，是为数不多的天然化合物之一，已知其能抑制与神经变性相关的蛋白质的淀粉样蛋白原纤维形成，并分解淀粉样蛋白原纤维。EGCG的分子作用机制，或它或其他小分子如何与淀粉样蛋白原纤维相互作用的机制鲜为人知。在这里，我们提出了一个3.9埃分辨率的cryoEM结构，该结构揭示了EGCG与AD脑源性tau原纤维结合的位点。该结构表明，EGCG通过楔入成对的螺旋丝的两个原丝界面处的裂缝，并引起原纤维的tau层之间排斥，从而使AD-tau的原纤维分解。为了支持这一点，我们观察到EGCG楔入的原丝的分离，以及伴随的相邻β-螺旋结构域的位移。