8FUG

Alzheimer's disease paired-helical filament in complex with PET tracer GTP-1

8FUG の概要

• エントリーDOI: 10.2210/pdb8fug/pdb
• EMDBエントリー: 29458
• 分子名称: Microtubule-associated protein tau, (5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole (2 entities in total)
• 機能のキーワード: neurodegeneration, positron emission tomography, filament, 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: 23
• 化学式量合計: 189485.48

構造登録者

Merz, G.E.,Tse, E.,Southworth, D.R. (登録日: 2023-01-17, 公開日: 2023-06-07, 最終更新日: 2024-06-19)

主引用文献

Merz, G.E.,Chalkley, M.J.,Tan, S.K.,Tse, E.,Lee, J.,Prusiner, S.B.,Paras, N.A.,DeGrado, W.F.,Southworth, D.R.
Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments.
Nat Commun, 14:3048-3048, 2023

PubMed Abstract: Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.

PubMed: 37236970
DOI: 10.1038/s41467-023-38537-y

実験手法

ELECTRON MICROSCOPY (2.7 Å)