Threonine Cavities Are Targetable Motifs That Control Alpha-Synuclein Fibril Growth.
Threonine Cavities Are Targetable Motifs That Control Alpha-Synuclein Fibril Growth.
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DOI：
10.1021/acschemneuro.2c00327
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发表时间：
2022-09-07
影响因子：
5
通讯作者：
Sachs, Jonathan N.
中科院分区：
文献类型：
--
作者：
Kochen, Noah Nathan;Vasandani, Vivek;Seaney, Darren;Pandey, Anil K.;Walters, Michael A.;Braun, Anthony R.;Sachs, Jonathan N.
最近α-突触核蛋白(ASyn)纤维的高分辨率结构为治疗帕金森氏病和路易体痴呆的药物发现提供了合理的方法。利用第一个这样的结构，我们之前使用了分子动力学和自由能计算来表明苏氨酸72和75-它们排列在纤维堆叠中充满水的空腔-可能在稳定纤维方面起着核心作用。在这里，我们使用野生型和A53T aSyn的实验性突变来表明这两个苏氨酸残基在纤维成核和伸长中发挥着重要但令人惊讶的不同作用。T72A突变体，而不是T75A，导致了初级成核过程中纤化程度的大幅增加，从而使我们假设T72对失控聚集起到了“刹车”的作用。一组对最近五个高分辨率纤维结构的扩展模拟表明，T72周围的空腔水的限制与这一发现相关。相反，T75A突变导致纤维化程度略有下降。此外，T72A和T75A都完全阻止了种子纤化过程中的初始原纤维伸长。为了测试这些苏氨酸衬里的空腔是否是可下药的目标，我们使用计算对接来识别潜在的小分子结合剂。我们表明，得分最高的热门药物，突起，强烈促进纤维生长，同时专门与Syn纤维而不是单体相互作用，我们提供了关于这些化合物如何被用于治疗的猜测。
Recent high-resolution structures of alpha-synuclein (aSyn) fibrils offer promise for rational approaches to drug discovery for Parkinson’s disease and Lewy body dementia. Harnessing the first such structures, we previously used molecular dynamics and free energy calculations to suggest that threonines 72 and 75—which line water-filled cavities within the fibril stacks—may be of central importance in stabilizing fibrils. Here, we used experimental mutagenesis of both wild-type and A53T aSyn to show that both threonine residues play important but surprisingly disparate roles in fibril nucleation and elongation. The T72A mutant, but not T75A, resulted in a large increase in the extent of fibrillization during primary nucleation, leading us to posit that T72 acts as a “brake” on run-away aggregation. An expanded set of simulations of five recent high-resolution fibril structures suggests that confinement of cavity waters around T72 correlates with this finding. In contrast, the T75A mutation led to a modest decrease in the extent of fibrillization. Furthermore, both T72A and T75A completely blocked the initial fibril elongation in seeded fibrillization. To test whether these threonine-lined cavities are druggable targets, we used computational docking to identify potential small-molecule binders. We show that the top-scoring hit, aprepitant, strongly promotes fibril growth while specifically interacting with aSyn fibrils and not monomer, and we offer speculation as to how such compounds could be used therapeutically.
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影响因子：
4.1
作者：
Luk, Kelvin C;Lee, Virginia M-Y
通讯作者：
Lee, Virginia M-Y
DOI：
10.1073/pnas.0407146102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Bertoncini, CW;Jung, YS;Zweckstetter, M
通讯作者：
Zweckstetter, M
影响因子：
4
作者：
Kamboj S;Harms C;Kumar L;Creamer D;West C;Klein-Seetharaman J;Sarkar SK
通讯作者：
Sarkar SK
影响因子：
3.4
作者：
Hazy, E.;Bokor, M.;Tompa, P.
通讯作者：
Tompa, P.
影响因子：
4.4
作者：
Gowers, Richard J.;Carbone, Paola
通讯作者：
Carbone, Paola