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首页> 外文期刊>Journal of Molecular Biology >NMR characterization of monomeric and oligomeric conformations of human calcitonin and its interaction with EGCG
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NMR characterization of monomeric and oligomeric conformations of human calcitonin and its interaction with EGCG

机译：降钙素的单体和低聚构象的NMR表征及其与EGCG的相互作用

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Calcitonin is a 32-residue peptide hormone known for its hypocalcemic effect and its inhibition of bone resorption. While calcitonin has been used in therapy for osteoporosis and Paget's disease for decades, human calcitonin (hCT) forms fibrils in aqueous solution that limit its therapeutic application. The molecular mechanism of fiber formation by calcitonin is not well understood. Here, high-resolution structures of hCT at concentrations of 0.3 mM and 1 mM have been investigated using NMR spectroscopy. Comparing the structures of hCT at different concentrations, we discovered that the peptide undergoes a conformational transition from an extended to a β-hairpin structure in the process of molecular association. This conformational transition locates the aromatic side chains of Tyr12 and Phe16 in a favorable way for intermolecular π-π stacking, which is proposed to be a crucial interaction for peptide association and fibrillation. One-dimensional 1H NMR experiments confirm that oligomerization of hCT accompanies the conformational transition at 1 mM concentration. The effect of the polyphenol epigallocatechin 3-gallate (EGCG) on hCT fibrillation was also investigated by NMR and electron microscopy, which show that EGCG efficiently inhibits fibril formation of hCT by preventing the initial association of hCT before fiber formation. The NMR experiments also indicate that the interaction between aromatic rings of EGCG and the aromatic side chains of the peptide may play an important role in inhibiting fibril formation of hCT.
机译：降钙素是32个残基的肽激素，因其降钙作用和抑制骨吸收作用而闻名。降钙素已被用于骨质疏松症和Paget病的治疗数十年，而人降钙素（hCT）在水溶液中会形成原纤维，从而限制了其治疗应用。降钙素形成纤维的分子机理尚不清楚。在这里，已经使用NMR光谱研究了浓度为0.3 mM和1 mM的hCT的高分辨率结构。比较不同浓度下的hCT结构，我们发现该肽在分子缔合过程中经历了从延伸到β-发夹结构的构象转变。该构象转变以分子间π-π堆积的有利方式定位了Tyr12和Phe16的芳族侧链，这被认为是肽缔合和原纤化的关键相互作用。一维1H NMR实验证实，hCT的低聚伴随着1 mM浓度的构象转变。还通过NMR和电子显微镜研究了多酚表没食子儿茶素3-没食子酸酯3-没食子酸酯对hCT原纤维形成的影响，这表明EGCG通过防止hCT在纤维形成之前的初始缔合而有效地抑制了hCT的原纤维形成。 NMR实验还表明，EGCG的芳香环与肽的芳香侧链之间的相互作用可能在抑制hCT的原纤维形成中起重要作用。

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