Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor.
Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor.
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DOI：
10.1038/nchem.1293
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发表时间：
2012-03-11
期刊：
影响因子：
21.8
通讯作者：
中科院分区：
文献类型：
--
作者：
虽然淀粉样蛋白的形成与二十多种人类疾病的病理有关，但淀粉样蛋白抑制剂的合理设计受到淀粉样蛋白抑制剂复合物结构信息缺乏的阻碍。我们使用同位素标记和二维红外光谱来获得人类胰淀素复合物的残基特异性结构，胰淀素是2型糖尿病中负责胰岛淀粉样蛋白形成的肽，具有已知的抑制剂大鼠胰淀素。根据其序列，大鼠胰淀素应该阻断c端β-片的形成，但在混合后8小时，大鼠胰淀素反而阻断了n端β-片的形成。混合24小时后，大鼠胰淀素既没有阻断β薄片，也没有在人体原纤维的外部形成自己的β薄片。这是惊人的，因为大鼠的胰淀素天生紊乱，以前不知道形成淀粉样蛋白β片。结果表明，即使是看似直观的抑制剂也可能通过不可预见的复杂结构过程起作用。
While amyloid formation has been implicated in the pathology of over twenty human diseases, the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labeling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin, the peptide responsible for islet amyloid formation in type 2 diabetes, with a known inhibitor, rat amylin. Based on its sequence, rat amylin should block formation of the C-terminal β-sheet, but at 8 hours after mixing rat amylin blocks the N-terminal β-sheet instead. At 24 hours after mixing, rat amylin blocks neither β-sheet and forms its own β-sheet most likely on the outside of the human fibrils. This is striking because rat amylin is natively disordered and not previously known to form amyloid β-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes.
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DOI：
10.1021/jp810261x
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Ling YL;Strasfeld DB;Shim SH;Raleigh DP;Zanni MT
通讯作者：
Zanni MT
影响因子：
2.9
作者：
Jayasinghe, SA;Langen, R
通讯作者：
Langen, R
影响因子：
2.9
作者：
Luca, Sorin;Yau, Wai-Ming;Tycko, Robert
通讯作者：
Tycko, Robert
影响因子：
16.2
作者：
Hollander, PA;Levy, P;Kolterman, OG
通讯作者：
Kolterman, OG
影响因子：
5.2
作者：
Marek, Peter;Woys, Ann Marie;Sutton, Kelvin;Zanni, Martin T.;Raleigh, Daniel P.
通讯作者：
Raleigh, Daniel P.