Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments
| Autor: | Merz, Gregory E, Chalkley, Matthew J, Tan, Sophia K, Tse, Eric, Lee, Joanne, Prusiner, Stanley B, Paras, Nick A, DeGrado, William F, Southworth, Daniel R |
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| Rok vydání: | 2023 |
| Předmět: |
Amyloid
Aging Cryoelectron Microscopy Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) tau Proteins Bioengineering Neurodegenerative Ligands Alzheimer's Disease Brain Disorders Alzheimer Disease Neurological Acquired Cognitive Impairment Humans 2.1 Biological and endogenous factors Dementia Generic health relevance Aetiology |
| Zdroj: | Nature communications, vol 14, iss 1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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