魔角旋转 NMR 研究流感 A M2(18-60)：对别构抑制机制的支持。
Magic angle spinning NMR investigation of influenza A M2(18-60): support for an allosteric mechanism of inhibition.
机构信息
Francis Bitter Magnet Laboratory and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
出版信息
J Am Chem Soc. 2010 Aug 18;132(32):10958-60. doi: 10.1021/ja101537p.
Abstract
The tetrameric M2 proton channel from influenza A virus conducts protons at low pH and is inhibited by aminoadamantyl drugs such as amantadine and rimantadine (Rmt). We report magic angle spinning NMR spectra of POPC and DPhPC membrane-embedded M2(18-60), both apo and in the presence of Rmt. Similar line widths in the spectra of apo and bound M2 indicate that Rmt does not have a significant impact on the dynamics or conformational heterogeneity of this construct. Substantial chemical shift changes for many residues in the transmembrane region support an allosteric mechanism of inhibition. An Rmt titration supports a binding stoichiometry of >1 Rmt molecule per channel and shows that nonspecific binding or changes in membrane composition are unlikely sources of the chemical shift changes. In addition, doubling of spectral lines in all of the observed samples provides evidence that the channel assembles with twofold symmetry.
摘要
来自甲型流感病毒的四聚体 M2 质子通道在低 pH 值下传导质子，并被金刚烷胺类药物如金刚烷胺和金刚乙胺（Rmt）抑制。我们报告了 POPC 和 DPhPC 膜嵌入 M2（18-60）的魔角旋转 NMR 光谱，包括apo 和存在 Rmt 的情况。apo 和结合的 M2 光谱中的相似线宽表明 Rmt 对该结构的动力学或构象异质性没有显著影响。跨膜区域中许多残基的大量化学位移变化支持抑制的变构机制。Rmt 滴定支持每个通道有 >1 个 Rmt 分子的结合计量，并表明非特异性结合或膜组成的变化不太可能是化学位移变化的来源。此外，所有观察到的样品中线谱的加倍提供了通道以二倍对称性组装的证据。
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