Quade Nick, Boehringer Daniel, Leibundgut Marc, van den Heuvel Joop, Ban Nenad
Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zürich, Zürich 8093, Switzerland.
Research Group Recombinant Protein Expression, Helmholtz Centre for Infection Research, Inhoffenstraße 7, Braunschweig 38124, Germany.
Nat Commun. 2015 Jul 8;6:7646. doi: 10.1038/ncomms8646.
Hepatitis C virus (HCV), a widespread human pathogen, is dependent on a highly structured 5'-untranslated region of its mRNA, referred to as internal ribosome entry site (IRES), for the translation of all of its proteins. The HCV IRES initiates translation by directly binding to the small ribosomal subunit (40S), circumventing the need for many eukaryotic translation initiation factors required for mRNA scanning. Here we present the cryo-EM structure of the human 40S ribosomal subunit in complex with the HCV IRES at 3.9 Å resolution, determined by focused refinement of an 80S ribosome-HCV IRES complex. The structure reveals the molecular details of the interactions between the IRES and the 40S, showing that expansion segment 7 (ES7) of the 18S rRNA acts as a central anchor point for the HCV IRES. The structural data rationalizes previous biochemical and genetic evidence regarding the initiation mechanism of the HCV and other related IRESs.
丙型肝炎病毒（HCV）是一种广泛传播的人类病原体，其所有蛋白质的翻译都依赖于其mRNA高度结构化的5'非翻译区，即内部核糖体进入位点（IRES）。HCV IRES通过直接与小核糖体亚基（40S）结合来启动翻译，从而无需mRNA扫描所需的许多真核生物翻译起始因子。在此，我们展示了通过对80S核糖体 - HCV IRES复合物进行聚焦精修，以3.9Å分辨率确定的与HCV IRES复合的人40S核糖体亚基的冷冻电镜结构。该结构揭示了IRES与40S之间相互作用的分子细节，表明18S rRNA的扩展片段7（ES7）作为HCV IRES的中心锚定点。这些结构数据使先前关于HCV及其他相关IRESs起始机制的生化和遗传证据合理化。
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