Towards a pharmacophore for amyloid.
Towards a pharmacophore for amyloid.
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DOI：
10.1371/journal.pbio.1001080
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发表时间：
2011-06
期刊：
影响因子：
9.8
通讯作者：
Eisenberg D
中科院分区：
文献类型：
--
作者：
Landau M;Sawaya MR;Faull KF;Laganowsky A;Jiang L;Sievers SA;Liu J;Barrio JR;Eisenberg D
尽管进行了深入的研究，但诊断和治疗阿尔茨海默氏症和其他与淀粉样纤维相关的疾病仍然是一个巨大的挑战。为了帮助在这方面的努力，我们目前的原子结构的纤维形成部分的蛋白质参与阿尔茨海默氏症的复杂的小分子粘合剂，确定通过X射线显微结晶。纤维状复合物由成对的β-片层组成，小分子结合在片层之间，大致平行于纤维轴。结构表明，非极性分子沿沿着纤维漂移，与观察到的非特异性结合到各种淀粉样蛋白相一致。相反，带负电荷的橙-G特异性结合到相邻片的赖氨酸侧链。这些结构为蛋白质聚集疾病的诊断和药物设计提供了分子框架。被称为阿尔茨海默病的毁灭性和不可治愈的痴呆症影响着全世界数千万人的思维，记忆和行为。虽然淀粉样蛋白纤维和两种蛋白质tau和淀粉样蛋白-β的寡聚体已被鉴定与这种疾病相关，但迄今为止，诊断和治疗的发展一直是在关于其结构的信息近乎真空的情况下进行的。在这里，我们报告的第一个原子结构的小分子结合淀粉样蛋白。这些是染料橙-G，天然化合物姜黄素和阿尔茨海默病诊断化合物DDNP结合到tau和淀粉样蛋白-β的淀粉样蛋白片段。这些结构揭示了小分子结合的分子框架，这些分子框架位于沿着纤维的β-棘延伸的圆柱形空腔内。带负电荷的橙-G楔入两片纤维之间的特定结合位点，将非极性结合与静电相互作用结合在一起，而不带电荷的化合物沿着空腔滑动。我们观察到不同的淀粉样蛋白多晶型结合不同的小分子，揭示了未来的淀粉样蛋白治疗可能需要混合化合物。这里描述的结构开始定义淀粉样蛋白药效团，开辟了基于结构的改进诊断和治疗设计的道路。
Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-β, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-β. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the β-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a cocktail of compounds may be required for future amyloid therapies. The structures described here start to define the amyloid pharmacophore, opening the way to structure-based design of improved diagnostics and therapeutics.
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影响因子：
2.9
作者：
Bayro, Marvin J.;Maly, Thorsten;Birkett, Neil R.;MacPhee, Cait E.;Dobson, Christopher M.;Griffin, Robert G.
通讯作者：
Griffin, Robert G.
影响因子：
9.8
作者：
Collins SR;Douglass A;Vale RD;Weissman JS
通讯作者：
Weissman JS
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
4.8
作者：
Chalifour, RJ;McLaughlin, RW;Gervais, F
通讯作者：
Gervais, F