STRUCTURAL BASIS OF CONTROLLING VIRUS CAPSID ASSEMBLY

控制病毒衣壳组装的结构基础

• 批准号: 8171995
• 负责人: Adam Zlotnick
• 金额: $ 1.09万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171995
• 关键词: Affect; Antiviral Agents; Binding Sites; Biology; Brome mosaic virus; Capsid; Capsid Proteins; Cessation of life; Chronic Hepatitis B; Collaborations; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Family; Funding; Gold; Grant; Hepatitis B Virus; Home environment; Hybrids; In Vitro; Indiana; Individual; Institution; Nanostructures; Nanotechnology; Plant Viruses; Proteins; Request for Proposals; Research; Research Personnel; Resolution; Resources; Sampling; Source; Structure; Thermodynamics; Time; United States; United States National Institutes of Health; Universities; Viral; Virion; Virus; Virus Assembly; Virus-like particle; base; improved; in vivo; insight; nanoparticle; particle; research study; small molecule; synchrotron radiation; therapeutic development; virus core

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding assembly of virus capsids has applications for understanding virus biology, development of assembly-directed antiviral therapeutics, and development of nanotechnology. In this proposal we request time to collect data on hepatitis B virus (HBV) capsids complexed with small molecules that affect assembly. This will define the respective binding sites of these assembly effectors and will allow us to deduce a mechanism of action. We will also acquire data for the structure of a plant virus capsid that was assembled on a nanoparticle core. This structure will provide insight into the virus-core interaction and as importantly provide a testbed for defining the experimental peculiarities of determining the structure of such hybrid particles. More than 350 million individuals suffer from chronic HBV, 1 million in the United States. HBV contributes 600,000 deaths each year. We have identified assembly of the HBV capsid as an antiviral target. In vivo, correct assembly is critical to viral replication. Recently we determined the structure of HBV capsids with a small molecule assembly effector and were able to determine the binding site and elucidate the thermodynamic basis of activity. We have identified a new family of effectors that induce assembly of smaller than normal capsids. Crystals of these complexes have diffracted up to 5.5¿ resolution on a home source; typically we have improved resolution of virus crystals by 1.5 to 2.5¿ using synchrotron radiation. We have also investigated assembly of virus-based nanostructures. In collaboration with Bogdan Dragnea (also at Indiana University), we have obtained crystals of Brome Mosaic Virus capsid protein that were assembled in vitro on a PEGylated gold nanoparticle. Here we can ask how intimately the protein and substrate interact. All samples used in these experiments are virus-like particles, not infectious virions.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 了解病毒capsids的组装有应用于理解病毒生物学，组装指导的抗病毒疗法的发展以及纳米技术的发展。在此提案中，我们要求时间收集有关丙型肝炎病毒（HBV）衣壳的数据，这些衣壳与影响组装的小分子复合在一起。这将定义这些组装效应的各自的结合位点，并使我们能够推断出一种作用机理。我们还将获取用于组装在纳米颗粒核心上的植物病毒衣壳结构的数据。这种结构将提供有关病毒核心相互作用的洞察力，并重要地提供了确定确定这种杂交颗粒结构的实验特殊性的测试台。 在美国，超过3.5亿人患有慢性HBV，100万人。 HBV每年造成600,000人死亡。我们已经将HBV衣壳的组装确定为抗病毒靶标。在体内，正确的组装对于病毒复制至关重要。最近，我们确定了具有小分子组装效应子的HBV衣壳的结构，并能够确定结合位点并阐明活性的热力学基础。我们已经确定了一个新的效应家族，该家族影响了比正常衣壳小于平常的组装。这些配合物的晶体在家庭源上的分辨率最高为5.5。通常，使用同步加速器辐射，我们将病毒晶体的分辨率提高了1.5至2.5。 我们还投资了基于病毒的纳米结构组装。我们与Bogdan Dragnea（也在印第安纳大学）合作，我们获得了Brome Mosaic病毒capsid蛋白的晶体，这些蛋白在体外聚集在Pegyper的金纳米粒子上。在这里，我们可以询问蛋白质和底物如何相互作用。 这些实验中使用的所有样品都是病毒样颗粒，而不是感染的病毒。