TY - JOUR T1 - CryoEM reveals how the small molecule EGCG binds to Alzheimer’s brain-derived tau fibrils and initiates fibril disaggregation JF - bioRxiv DO - 10.1101/2020.05.29.124537 SP - 2020.05.29.124537 AU - PM Seidler AU - DR Boyer AU - MR Sawaya AU - P Ge AU - WS Shin AU - MA DeTure AU - DW Dickson AU - L Jiang AU - DS Eisenberg Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/05/30/2020.05.29.124537.abstract N2 - 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 Å resolution cryoEM structure that reveals the site of EGCG binding to Alzheimer’s disease (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 β-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.Competing Interest StatementPotential conflicts of interest: David S. Eisenberg is chair and equity holder of ADRx, Inc. ER -