While polymorphism of fibrils adds complexity to the characterizazion of their role in neurodegeneration, it creates an opportunity for developing tau-selective ligands to target disease-specific fibrils. Tau positron-emission tomography (PET) ligands allow visualization of fibrils inside the brain. Structural insights into the mode of binding of such ligands to disease-related tau filaments are essential to help guide ligand optimization. Writing in Nature Communications, Merz et al.1 report cryo-EM structure of tau fibrils derived from patients with Alzheimer’s disease bound to the PET ligand GTP-1, a second-generation tau PET tracer currently in clinical trials. Yielding a 2.7-Å resolution, the structure resembles that of the paired helical filaments obtained from brain tissues of individuals with Alzheimer’s disease1, in which two C-shaped protofilaments interact laterally to form fibrils, and provides insights into the mode of GTP-1 binding (see figure). The additional, well-resolved density allowed the identification of the ligand bound to a solvent-exposed C-shaped cleft in each protofilament. This region in the fibrils comprises residues within the amyloid core (pseudo-repeats R3 and R4) and includes strands β6 and β7. These β-strands are separated by a kink at Gly355, which contributes to the formation of a cleft matching the convex shape of GTP-1. By combining molecular dynamics simulations and density functional theory, the authors revealed a remarkable geometrical and physical complementarity between GTP-1 and the cleft within tau PHF. GTP-1 comprises a tricyclic aromatic ring system, a piperidine ring and a fluoroethyl tail (left panel). With a 1:1 stoichiometry, GTP-1 interacts with tau PHF through π–π stacking, precisely matching its phenyl ring with the side chains of the residues in the binding site. Importantly, a specific orientation of the piperazine ring perpendicular to the symmetry of the fibrils is observed. This precise matching between GTP-1 and its cleft might be the basis for its high affinity and specificity.
These results suggest that a specific ligand orientation, in which the aromatic rings are angled relative to the symmetry of the fibrils, might be key in determining high affinity, and thus may be a common motif in future small molecules binding to filaments. At the same time, the geometrical and physical matching between GTP-1 and tau PHF might underlie their selectivity for Alzheimer’s-disease-specific filaments.
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