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

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.

Insight into the Binding of First- and Second-Generation PET Tracers to 4R and 3R/4R Tau Protofibrils

“…The CBD protofibril also exhibits a similar surface site s9 that is constituted by two basic residues and shows good stability for tracer binding. For the AD tau protofibril, the concave sites are the most identified sites for the PET tracer binding from experimental research. , The V4 site has two basic residues on the two sides; however, H362 and K269 are separated by 7 residues. Looking into the sites ranked between the top 3 and top 6 from the simulations starting from V3 and V4, we can identify a certain amount of exchange of tracer binding between the two sites (Figure A).…”

“…For the AD tau protofibril, the concave sites are the most identified sites for the PET tracer binding from experimental research. 28,40 The V4 site has two basic residues on the two sides; however, H362 and K269 are separated by 7 residues.…”

“…A very recent paper 40 has shown a novel and interesting binding mode that multiple GTP1 molecules can be stacked along the axis of the fibril in the groove site of the AD tau fibril with a very high concentration of tracer, indicating that ligand cooperativity can compensate for the instability of these half (the V2 and V3 sites in the AD protofibril) solvent-exposed binding sites. This also implies a further consideration of the possibility of ligand cooperativity in the fully solvent-exposed surface sites for the 4R tau fibrils.…”

Docking for molecules that bind in a symmetric stack with SymDOCK

“…2). 19 For each pose that passes the symmetry check, we add the van der Waals interaction of the original molecule and the transformed version to the total DOCK score function, with the same AMBER 4.0 united-atom force field parameters as the ligand-protein van der Waals energy. 31,[39][40][41] Figure 1.…”

“…18 The positron emission tomography (PET) radiotracers GTP-1 and MK-6240 bind within the "C" shape of each protofilament with the same stoichiometry, as does flortaucipir (Tauvid) to CTE Type I tau. [19][20][21][22] In each of these examples, the ligands within the stacks make substantial van der Waals and π-π interactions. Intriguingly, for the PET tracers, these ligand-ligand interactions seem more dominant than their direct contacts with the fibrils.…”