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

具有 PET 配体 MK - 6240 的阿尔茨海默病 tau 丝的冷冻 EM 结构。

• 发表时间: 2023 Sep 22
• 来源期刊: bioRxiv
• DOI: 10.1101/2023.09.22.558671
• PMID: 37790438
• 文章类型: Preprint
• 作者列表: Kunach P,Vaquer-Alicea J,Smith MS,Hopewell R,Monistrol J,Moquin L,Therriault J,Tissot C,Rahmouni N,Massarweh G,Soucy JP,Guiot MC,Shoichet BK,Rosa-Neto P,Diamond MI,Shahmoradian SH

关键词: Alzheimer’s disease (AD); Cryo-electron microscopy (cryo-EM); Neurofibrillary tangles (NFTs); Positron emission tomography (PET); Tau; [18F]MK-6240 PET tracer; atomic resolution; autoradiography; binding affinity; binding agents; in vivo PET imaging; pi-pi aromatic stacking

Abstract

Positron Emission Tomography (PET) ligands have advanced Alzheimer\'s 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 Å 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.

摘要

正电子发射断层扫描（PET）配体具有晚期阿尔茨海默病（AD）的诊断和治疗作用。使用放射自显影和冷冻EM，我们发现AD脑组织tau负荷升高,纯化的长丝，并确定了第二代高亲和力PET配体MK-6240的结构，分辨率为2.31。在tau配对螺旋丝（PHF）的裂口内以1：1的比例结合，使用谷氨酰胺351，赖氨酸K353和异亮氨酸360。该信息阐明了MK-6240PET在量化AD中的PHF沉积物中的基础，并且可以促进针对tau淀粉样蛋白的优异配体的基于结构的设计。