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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure of a hepatitis C virus RNA domain in complex with a translation inhibitor reveals a binding mode reminiscent of riboswitches
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Structure of a hepatitis C virus RNA domain in complex with a translation inhibitor reveals a binding mode reminiscent of riboswitches

机译:与翻译抑制剂复合的丙型肝炎病毒RNA结构域的结构揭示了结合模式,让人联想到核糖开关

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摘要

The internal ribosome entry site (IRES) in the hepatitis C virus (HCV) RNA genome is essential for the initiation of viral protein synthesis. IRES domains adopt well-defined folds that are potential targets for antiviral translation inhibitors. We have determined the three-dimensional structure of the IRES subdomain Ma in complex with a benzimidazole translation inhibitor at 2.2 A resolution. Comparison to the structure of the unbound RNA in conjunction with studies of inhibitor binding to the target in solution demonstrate that the RNA undergoes a dramatic ligand-induced conformational adaptation to form a deep pocket that resembles the substrate binding sites in riboswitches. The presence of a well-defined ligand-binding pocket within the highly conserved IRES subdomain Ha holds promise for the development of unique anti-HCV drugs with a high barrier to resistance.
机译:丙型肝炎病毒(HCV)RNA基因组中的内部核糖体进入位点(IRES)对于启动病毒蛋白合成至关重要。 IRES结构域采用明确定义的折叠,这是抗病毒翻译抑制剂的潜在目标。我们已经确定了在2.2 A分辨率下与苯并咪唑翻译抑制剂复合的IRES子域Ma的三维结构。与未结合RNA的结构相比较,结合抑制剂与溶液中靶标结合的研究,证明该RNA经历了引人注目的配体诱导的构象适应,形成了类似于核糖开关中底物结合位点的深袋。在高度保守的IRES亚结构域Ha中存在明确定义的配体结合口袋,有望开发出具有高耐药性屏障的独特抗HCV药物。

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  • 作者单位

    Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093;

    Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093;

    Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093;

    Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182;

    Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182;

    Division of Infectious Diseases, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093;

    Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093;

  • 收录信息 美国《科学引文索引》(SCI);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
  • 关键词

    crystallography; hepatitis C virus inhibitor; RNA structure;

    机译:晶体学丙型肝炎病毒抑制剂;RNA结构;

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