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Unusual architecture of the p7 channel from hepatitis C virus

机译：丙型肝炎病毒p7通道的异常结构

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摘要

The hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations. We wanted to examine the structural solution that the viroporin adopts in order to achieve selective cation conduction, because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The activity of p7 can be inhibited by amantadine and rimantadine, which are potent blockers of the influenza M2 channel and licensed drugs against influenza infections. The adamantane derivatives have been used in HCV clinical trials8, but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here we determine the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbours, but also reach farther to associate with the i+ 2 and i+ 3 monomers, forming a sophisticated, funnel-like architecture. The structure also points to a mechanism of cation selection: an asparagine/ histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter, whereas an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording shows that these residues are critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide a molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives.%丙肝病毒(HCV)是肝病和肝癌的一个主要病因。由于没有保护性疫苗，也由于治疗方案仍然有限，寻找新的治疗目标便显得很重要。James Chou及其同事在这篇论文中报告了低聚丙肝病毒“viroporin p7”的结构，是通过NMR谱获得的。该蛋白能自组成一个可传导阳离子的通道复合物。该通道六聚物的一个高分辨率视图显示了新颖的漏斗状通道结构，而功能研究则识别出了对通道活性重要的残体。
机译：丙型肝炎病毒（HCV）已开发出一种小的膜蛋白p7，该蛋白可以自组装成能选择性传导阳离子的大通道复合物。我们希望检查维罗帕林为了实现选择性阳离子传导而采用的结构解决方案，因为p7与任何已知的原核或真核通道蛋白均不具有同源性。 p7的活性可以被金刚烷胺和金刚烷胺抑制，金刚烷胺和金刚烷胺是M2流感通道的有效阻滞剂，并且是针对流感感染的许可药物。金刚烷衍生物已用于HCV临床试验8，但如果没有详细的分子结构，则很难解释各种HCV基因型之间药物疗效的巨大差异。在这里，我们使用最新的核磁共振（NMR）技术确定此HCV维普罗林的结构及其药物结合位点。该结构表现出不寻常的六聚体组装模式，其中单个p7单体i不仅与其相邻邻域相互作用，而且还与i + 2和i + 3单体缔合得更远，从而形成了复杂的漏斗状结构。该结构还指出了阳离子选择的机制：收缩漏斗窄端的天冬酰胺/组氨酸环用作宽阳离子选择性过滤器，而定义漏斗宽端的精氨酸/赖氨酸环可以选择性地允许阳离子扩散到通道中。我们使用全细胞通道记录的功能研究表明，这些残基对于通道活性至关重要。通道-药物复合物的NMR测量显示，金刚烷胺或金刚烷胺结合的外围螺旋和成孔螺旋之间有六个等效的疏水口袋，与该位置特异性结合的化合物可通过阻止通道打开来变构抑制阳离子传导。我们的数据为p7介导的阳离子电导及其对金刚烷衍生物的抑制作用提供了分子解释。％丙肝病毒（HCV）是肝病和肝癌的一个主要病因。由于没有保护性疫苗，也由于治疗方案仍然有限，寻找新的詹姆斯·周及其同事在这篇论文中报告了低聚丙肝病毒“ viroporin p7”的结构，是通过NMR谱获得的。该蛋白能自组成一个可以取代的通道复合物。该通道六常数的一个整体视图显示了新颖的漏斗状通道结构，而功能研究则识别出了对通道活性重要的残体。

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  • 来源
    《Nature》 |2013年第7455期|521-525397|共6页
  • 作者

    Bo Oil Yang; Shiqi Xie; Marcelo J. Berardi; Xinhao Zhao; Jyoti Dev; Wenjing Yu; Bing Sun; James J. Chou;

  • 作者单位

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA, State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China, National Center for Protein Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.;

    Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.;

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.;

    Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.;

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.;

    Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.;

    Molecular Virus Unit, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China;

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA, State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China, National Center for Protein Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.;

  • 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);
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