Orientation of a Diagnostic Ligand Bound to Macroscopically Aligned Amyloid-ß Fibrils Determined by Solid-State NMR
Orientation of a Diagnostic Ligand Bound to Macroscopically Aligned Amyloid-ß Fibrils Determined by Solid-State NMR
复制标题
通过固态 NMR 确定与宏观排列的淀粉样蛋白原纤维结合的诊断配体的方向
DOI：
10.1021/acs.jpclett.8b02448
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Townsend D
中科院分区：
文献类型：
--
作者：
Townsend D
淀粉样蛋白疾病即将成为人口老龄化国家的主要健康负担，有助于在体外和体内检测淀粉样蛋白的诊断分子具有相当大的临床价值。了解这些配体如何识别其淀粉样蛋白靶标将有助于设计针对与特定疾病相关的特定淀粉样蛋白类型的诊断方法，但提供全面信息的方法尚不发达。在这里，固态核磁共振被用来确定淀粉样蛋白诊断1-氟-2,5-二[(E)-3-羧基-4-羟基苯基]-苯（FSB）与阿尔茨海默氏淀粉样蛋白-β多肽在平面底物上排列的纤维结合时的分子取向。排列配合物的19f NMR谱显示，FSB取向近似平行于纤维长轴，并桥接了四个氢键β-片。除了提供原子细节以帮助设计淀粉样蛋白特异性诊断外，该方法还将阐明淀粉样蛋白疾病中辅助分子的分子机制。
With amyloid diseases poised to become a major health burden in countries with aging populations, diagnostic molecules that aid the detection of amyloid in vitro and in vivo are of considerable clinical value. Understanding how such ligands recognize their amyloid targets would help to design diagnostics that target specific amyloid types associated with a particular disease, but methods to provide comprehensive information are underdeveloped. Here, solid-state NMR is used to determine the molecular orientation of the amyloid diagnostic 1-fluoro-2,5-bis[(E)-3-carboxy-4-hydroxystyryl]-benzene (FSB) when bound to fibrils of the Alzheimer’s amyloid-β polypeptide aligned on a planar substrate. The19F NMR spectrum of the aligned complex reveals that FSB is oriented approximately parallel with the fibril long axis and bridges four hydrogen-bonded β-sheets. In addition to providing atomic details to aid the design of amyloid-specific diagnostics, this approach will also illuminate the molecular mechanisms of accessory molecules in amyloid disease.