8FUG

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

Summary for 8FUG

• Entry DOI: 10.2210/pdb8fug/pdb
• EMDB information: 29458
• Descriptor: Microtubule-associated protein tau, (5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole (2 entities in total)
• Functional Keywords: neurodegeneration, positron emission tomography, filament, alzheimer's disease, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 23
• Total formula weight: 189485.48

Authors

Merz, G.E.,Tse, E.,Southworth, D.R. (deposition date: 2023-01-17, release date: 2023-06-07, Last modification date: 2024-06-19)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.7 Å)