Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.
Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.
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具有 PET 配体 MK-6240 的阿尔茨海默病 tau 丝的冷冻电镜结构。
DOI：
10.1101/2023.09.22.558671
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发表时间：
2023
期刊：
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作者：
Kunach,Peter;Vaquer-Alicea,Jaime;Smith,MatthewS;Hopewell,Robert;Monistrol,Jim;Moquin,Luc;Therriault,Joseph;Tissot,Cecile;Rahmouni,Nesrine;Massarweh,Gassan;Soucy,Jean-Paul;Guiot,Marie-Christine;Shoichet,BrianK;Rosa-Neto,Pedro;
正电子发射断层扫描（PET）配体具有先进的阿尔茨海默病（AD）诊断和治疗。使用放射自显影和冷冻EM，我们鉴定了tau负荷升高的AD脑组织，纯化细丝，并以2.31 μ m的分辨率确定了第二代高亲和力PET配体MK-6240的结构，其以1：1的比例结合在tau配对螺旋细丝（PHF）的裂缝内，与谷氨酰胺351，赖氨酸353和异亮氨酸360接合。该信息阐明了MK-6240 PET定量AD中PHF沉积的基础，并可能有助于基于结构设计抗tau淀粉样蛋白的上级配体。
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.