8UQ7

Alzheimer's disease PHF complexed with PET ligand MK-6240

Summary for 8UQ7

• Entry DOI: 10.2210/pdb8uq7/pdb
• EMDB information: 42463
• Descriptor: Microtubule-associated protein tau, 6-fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (2 entities in total)
• Functional Keywords: mk-6240 pet ligand, ad phf, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 50776.18

Authors

Kunach, P.,Shahmoradian, S.H.,Diamond, M.I.,Rosa-Neto, P. (deposition date: 2023-10-23, release date: 2024-09-04, Last modification date: 2024-10-23)

Primary citation

Kunach, P.,Vaquer-Alicea, J.,Smith, M.S.,Monistrol, J.,Hopewell, R.,Moquin, L.,Therriault, J.,Tissot, C.,Rahmouni, N.,Massarweh, G.,Soucy, J.P.,Guiot, M.C.,Shoichet, B.K.,Rosa-Neto, P.,Diamond, M.I.,Shahmoradian, S.H.
Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.
Nat Commun, 15:8497-8497, 2024

PubMed 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.

PubMed: 39353896
DOI: 10.1038/s41467-024-52265-x

Experimental method

ELECTRON MICROSCOPY (2.31 Å)