7UPE

Tau Paired Helical Filament from Alzheimer's Disease not incubated with EGCG

7UPE の概要

• エントリーDOI: 10.2210/pdb7upe/pdb
• 関連するPDBエントリー: 7UPF
• EMDBエントリー: 26663
• 分子名称: Isoform Tau-F of Microtubule-associated protein tau (1 entity in total)
• 機能のキーワード: amyloid, fibril, alzheimer's, disease, protein fibril
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 459198.71

構造登録者

Seidler, P.M.,Murray, K.A.,Boyer, D.R.,Ge, P.,Sawaya, M.R.,Eisenberg, D.S. (登録日: 2022-04-15, 公開日: 2022-09-28, 最終更新日: 2024-06-12)

主引用文献

Seidler, P.M.,Murray, K.A.,Boyer, D.R.,Ge, P.,Sawaya, M.R.,Hu, C.J.,Cheng, X.,Abskharon, R.,Pan, H.,DeTure, M.A.,Williams, C.K.,Dickson, D.W.,Vinters, H.V.,Eisenberg, D.S.
Structure-based discovery of small molecules that disaggregate Alzheimer's disease tissue derived tau fibrils in vitro.
Nat Commun, 13:5451-5451, 2022

PubMed Abstract: Alzheimer's disease (AD) is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. Thus disaggregation of tau fibrils could be a therapeutic approach to AD. The small molecule EGCG, abundant in green tea, has long been known to disaggregate tau and other amyloid fibrils, but EGCG has poor drug-like properties, failing to fully penetrate the brain. Here we have cryogenically trapped an intermediate of brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregation and have determined its cryoEM structure. The structure reveals that EGCG molecules stack in polar clefts between the paired helical protofilaments that pathologically define AD. Treating the EGCG binding position as a pharmacophore, we computationally screened thousands of drug-like compounds for compatibility for the pharmacophore, discovering several that experimentally disaggregate brain-derived tau fibrils in vitro. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases.

PubMed: 36114178
DOI: 10.1038/s41467-022-32951-4

実験手法

ELECTRON MICROSCOPY (3.4 Å)