STRUCTURE OF PESTIVIRUS ENVELOPE PROTEINS

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 表示子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目的总体目标是了解瘟病毒家族成员如何组装，以及它们如何进入宿主细胞。我们专注于包膜病毒进入细胞的关键步骤：病毒和宿主细胞膜的融合。膜融合是包膜病毒进入细胞的重要步骤，因为它将病毒基因组递送到细胞质中。我们以前已经确定了前和后融合结构的融合后的几个包膜蛋白从相关的黄病毒家族。这些结构对这些病毒的膜融合机制产生了重要的见解。然而，黄病毒和瘟病毒具有实质上不同的包膜蛋白，并且瘟病毒包膜蛋白预计将采用新型蛋白折叠。膜融合的机制也可能以显著的方式不同。目前没有任何瘟病毒结构蛋白的结构信息（只有所谓的非结构蛋白的结构可用）。为了更好地了解瘟病毒组装和细胞进入，我们建议确定三种不同的肝病毒包膜蛋白的结构。我们的瘟病毒包膜蛋白的结构将推进我们对瘟病毒组装和细胞进入的理解。瘟病毒对牲畜造成严重损害，并与重要的人类病原体如丙型肝炎病毒有关。我们的工作将提供对形成瘟病毒蛋白外壳的蛋白质的第一个结构见解。直接观察这种外部蛋白质外壳对于理解瘟病毒如何组装其蛋白质外壳至关重要，并且将揭示暴露在病毒表面上的蛋白质表位的精确性质和范围。这将为合理设计抗病毒化合物提供一个框架，即病毒膜融合，或病毒附着到细胞上。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall goal of this project is to understand how members of the Pestivirus family assemble, and how they enter the host cell. We focus on a key step in the entry of enveloped viruses into the cell: fusion of the viral and host cell membranes. Membrane fusion is an essential step in entry of enveloped viruses because it delivers the viral genome into the cytoplasm. We have previously determined the pre- and postfusion structures of the postfusion of several envelope proteins from the related flavivirus family. These structures yielded important insights into the membrane fusion mechanism of these viruses. However, flaviviruses and pestiviruses have substantially divergent envelope proteins, and the pestivirus envelope proteins are expected to adopt novel protein folds. The mechanism of membrane fusion may also differ in significant ways. There is currently no structural information of any pestivirus structural protein (only structure of the so-called non-structural proteins are available). In order to gain a better understanding of pestivirus assembly and cell entry, we propose to determine the structure of three different hepacivirus envelope proteins. Our structures of pestivirus envelope proteins will advance our understanding of pestivirus assembly and cell entry. Pestiviruses cause serious damage to livestock and are related to important human pathogens such as Hepatitis C virus. Our work will provide the first structural insight into the proteins that form the outer protein shell of pestiviruses. A direct view of this outer protein shell is essential for understanding how pestiviruses assemble their protein coats, and will reveal the precise nature and extent of the protein epitopes that are exposed on the viral surface. This will provide a framework for the rational design of antiviral compounds that viral membrane fusion, or viral attachment to the cell.