Nature CommunicationsNeurosciencePeer-reviewed journal article
Cryo-EM structure of Alzheimer disease tau filaments with PET ligand MK-6240
Peter KunachiD, Jaime Vaquer‐AliceaiD, Matthew S. SmithiD, Jim MonistroliD, Robert HopewelliD, Luc Moquin, Joseph TherriaultiD, Cécile TissotiD, Nesrine RahmouniiD, Gassan MassarwehiD, Jean‐Paul SoucyiD, Marie‐Christine Guiot, Brian K. ShoichetiD, Pedro Rosa‐NetoiD, Marc I. DiamondiD, Sarah H. ShahmoradianiD
Abstract
Positron Emission Tomography (PET) ligands have advanced Alzheimers disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined the structure of second-generation high avidity PET ligand MK-6240 at 2.31 [A] resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine K353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.
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