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TitleStacked binding of a PET ligand to Alzheimer's tau paired helical filaments.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3048, Year 2023
Publish dateMay 26, 2023
AuthorsGregory E Merz / Matthew J Chalkley / Sophia K Tan / Eric Tse / Joanne Lee / Stanley B Prusiner / Nick A Paras / William F DeGrado / Daniel R Southworth /
PubMed AbstractAccumulation 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- ...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.
External linksNat Commun / PubMed:37236970 / PubMed Central
MethodsEM (helical sym.)
Resolution2.7 Å
Structure data

29458

8fug

EMDB-29458, PDB-8fug:
Alzheimer's disease paired-helical filament in complex with PET tracer GTP-1
Method: EM (helical sym.) / Resolution: 2.7 Å

Chemicals

ChemComp-Y9H:
(5S)-2-[4-(2-fluoroethyl)piperidin-1-yl]pyrimido[1,2-a]benzimidazole

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / Neurodegeneration / Positron Emission Tomography / Filament / Alzheimer's disease

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