Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments

Gregory E. Merz, Matthew J. Chalkley, Sophia K. Tan, Eric Tse, Joanne Lee, Stanley B. Prusiner, Nick A. Paras, William F. DeGrado and Daniel R. Southworth ()
Additional contact information
Gregory E. Merz: University of California San Francisco
Matthew J. Chalkley: University of California San Francisco
Sophia K. Tan: University of California San Francisco
Eric Tse: University of California San Francisco
Joanne Lee: University of California San Francisco
Stanley B. Prusiner: University of California San Francisco
Nick A. Paras: University of California San Francisco
William F. DeGrado: University of California San Francisco
Daniel R. Southworth: University of California San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38537-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38537-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38537-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().