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

Kunach, P.; Vaquer-Alicea, J.; Smith, M. S.; Hopewell, R.; Monistrol, J.; Moquin, L.; Therriault, J.; Tissot, C.; Rahmouni, N.; Massarweh, G.; Soucy, J.-P.; Guiot, M.-C.; Shoichet, B. K.; Rosa-Neto, P. K.; Diamond, M. I.; Shahmoradian, S. H.

doi:10.1101/2023.09.22.558671

bioRxiv · 10.1101/2023.09.22.558671

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

Kunach, P.·Vaquer-Alicea, J.·Smith, M. S.·Hopewell, R.·Monistrol, J.·Moquin, L.·Therriault, J.·Tissot, C.·Rahmouni, N.·Massarweh, G.·Soucy, J.-P.·Guiot, M.-C.·Shoichet, B. K.·Rosa-Neto, P. K.·Diamond, M. I.·Shahmoradian, S. H.

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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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Kunach, P., Vaquer-Alicea, J., Smith, M. S., Hopewell, R., Monistrol, J., Moquin, L., Therriault, J., Tissot, C., Rahmouni, N., Massarweh, G., Soucy, J.-P., Guiot, M.-C., Shoichet, B. K., Rosa-Neto, P. K., Diamond, M. I., Shahmoradian, S. H.. 2023-09-22. Cryo-EM structure of Alzheimer disease tau filaments with PET ligand MK-6240. https://doi.org/10.1101/2023.09.22.558671

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