ROTATIONAL RESONANCE SOLID-STATE NMR ELUCIDATES A STRUCTURAL MODEL OF PANCREATIC AMYLOID
ROTATIONAL RESONANCE SOLID-STATE NMR ELUCIDATES A STRUCTURAL MODEL OF PANCREATIC AMYLOID
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DOI：
10.1021/ja00117a023
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发表时间：
1995-03-29
影响因子：
15
通讯作者：
LANSBURY, PT
中科院分区：
文献类型：
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作者：
GRIFFITHS, JM;ASHBURN, TT;LANSBURY, PT
旋转共振（R(2)）固态核磁共振光谱测量了基于人类胰岛淀粉样蛋白多肽（amylin， IAPP(H)）残基20-29的由c -13标记的肽类似物(achn - snnfgaailss - conh2， IAPP（H)(20-29)）组成的淀粉样蛋白原纤维中的6个碳间距离。分子内碳间距离限制了肽骨架二面角（phi, psi），表明IAPP(H)（20-29）在淀粉样蛋白纤维中采用高度褶皱的β片结构。这种结构比Pauling用来描述丝纤维的反平行β片模型更紧凑。夸张的褶皱可能允许疏水侧链之间的链内范德华相互作用。在标记稀释实验中观察到的定性分子间R(2)效应可以模拟链间相互作用。在Ala25的C- α和Ile26的C=O之间观察到分子间的R(2)效应，表明它们在淀粉样蛋白β薄片中接近。R(2) sssnmr测量允许改进我们的IAPP(H)（20-29）淀粉样蛋白薄片的二维模型。改进后的模型可能有助于设计与胰腺淀粉样蛋白结合的分子。这些分子可能对ii型糖尿病的诊断或治疗有用。
Rotational resonance (R(2)) solid-state NMR spectroscopy was used to measure six intercarbon distances in amyloid fibrils comprising C-13-labeled analogs of a peptide (AcHN-SNNFGAILSS-CONH2, IAPP(H)(20-29)) based on residues 20-29 of the human islet amyloid polypeptide (amylin, IAPP(H)). The intramolecular intercarbon distances, which constrain the peptide backbone dihedral angles (phi, psi), suggest that IAPP(H)(20-29) adopts a highly pleated beta sheet structure in the amyloid fibril. This structure is more compact than the antiparallel beta sheet model formulated by Pauling to describe the silk fibril. Exaggerated pleating may allow intrastrand van der Waals interactions between hydrophobic side chains. Interstrand interactions can be modeled using qualitative intermolecular R(2) effects which are observed in label dilution experiments. An intermolecular R(2) effect was observed between the C-alpha of Ala25 and the C=O of Ile26, suggesting their proximity in the amyloid beta sheet. The R(2) SSNMR measurements allow the refinement of our two-dimensional model of the IAPP(H)(20-29) amyloid beta sheet. The refined model may facilitate the design of molecules that bind to pancreatic amyloid. Such molecules may be useful as diagnostics or therapeutics for type-II diabetes.