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Structure and mechanism of the M2 proton channel of influenza A virus

机译：甲型流感病毒M2质子通道的结构和机制

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摘要

The integral membrane protein M2 of influenza virus forms pH-gated proton channels in the viral lipid envelope. The low pH of an endosome activates the M2 channel before haemagglutinin-mediated fusion. Conductance of protons acidifies the viral interior and thereby facilitates dissociation of the matrix protein from the viral nucleoproteins-a required process for unpacking of the viral genome. In addition to its role in release of viral nucleoproteins, M2 in the trans-Golgi network (TGN) membrane prevents premature con formational rearrangement of newly synthesized haemagglutinin during transport to the cell surface by equilibrating the pH of the TGN with that of the host cell cytoplasm. Inhibiting the proton conductance of M2 using the anti-viral drug amantadine or rimantadine inhibits viral replication. Here we present the structure of the tetrameric M2 channel in complex with rimantadine, determined by NMR. In the closed state, four tightly packed transmembrane helices define a narrow channel, in which a 'tryptophan gate' is locked by intermolecular interactions with aspartic acid. A carboxy-terminal, amphipathic helix oriented nearly perpendicular to the transmembrane helix forms an inward-facing base. Lowering the pH destabilizes the transmembrane helical packing and unlocks the gate, admitting water to conduct protons, whereas the C-terminal base remains intact, preventing dissociation of the tetramer. Rimantadine binds at four equivalent sites near the gate on the lipid-facing side of the channel and stabilizes the closed conformation of the pore. Drug-resistance mutations are predicted to counter the effect of drug binding by either increasing the hydrophilicity of the pore or weakening helix-helix packing, thus facilitating channel opening.
机译：流感病毒的整合膜蛋白M2在病毒脂质包膜中形成pH门控质子通道。在血凝素介导的融合之前，内体的低pH值会激活M2通道。质子的传导酸化了病毒内部，从而促进了基质蛋白与病毒核蛋白的分离，这是解开病毒基因组的必要过程。反转录高尔基网（TGN）膜中的M2除了在释放病毒核蛋白方面发挥作用外，还可以通过平衡TGN的pH值和宿主细胞的pH值，防止新合成的血凝素在运输到细胞表面期间过早的构象重排。细胞质。使用抗病毒药物金刚烷胺或金刚乙胺抑制M2的质子传导可抑制病毒复制。在这里，我们介绍了与金刚烷胺复合的四聚体M2通道的结构，通过NMR测定。在闭合状态下，四个紧密堆积的跨膜螺旋限定了一个狭窄的通道，其中的“色氨酸门”通过与天冬氨酸的分子间相互作用而被锁定。几乎垂直于跨膜螺旋取向的羧基末端两亲螺旋形成向内的碱基。降低pH值会破坏跨膜螺旋填料的稳定性并解锁门，使水传导质子，而C端碱基则保持完整，从而防止四聚体解离。金刚烷胺在通道的面向脂质侧的门附近的四个等效位点处结合，并稳定孔的闭合构象。预测耐药性突变可通过增加孔的亲水性或减弱螺旋-螺旋堆积来抵消药物结合的作用，从而促进通道开放。

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  • 来源
    《Nature》 |2008年第7178期|p.591-595|共5页
  • 作者

    Jason R. Schnell; James J. Chou;

  • 作者单位
  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 自然科学总论;
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