Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240

oleh: Peter Kunach, Jaime Vaquer-Alicea, Matthew S. Smith, Jim Monistrol, Robert Hopewell, Luc Moquin, Joseph Therriault, Cecile Tissot, Nesrine Rahmouni, Gassan Massarweh, Jean-Paul Soucy, Marie-Christine Guiot, Brian K. Shoichet, Pedro Rosa-Neto, Marc I. Diamond, Sarah H. Shahmoradian

Format: Article
Diterbitkan: Nature Portfolio 2024-10-01

Deskripsi

Abstract Positron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, 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.