STRUCTURAL BIOLOGY OF JCV HOST CELL RECOGNITION

JCV宿主细胞识别的结构生物学

• 批准号: 8512815
• 负责人: THILO STEHLE
• 金额: $ 17.44万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8512815
• 关键词: Adopted; Affect; Affinity; Antiviral Agents; Area; Binding; Biological Assay; Capsid; Capsid Proteins; Carbohydrates; Cell Surface Receptors; Cells; Cocrystallography; Complex; Crystallization; Data; Defensins; Detection; Development; Disease; Docking; Enzyme-Linked Immunosorbent Assay; Foundations; Gangliosides; HDAC5 gene; Human; Individual; Infection; JC Virus; Knowledge; Laboratories; Lead; Ligand Binding; Ligands; Mediating; Molecular; Molecular Models; Mutation; N-terminal; Oligosaccharides; Organ; Pathogenesis; Peptides; Polyomavirus; Polyomavirus Infections; Polysaccharides; Proteins; Research; Resolution; Roentgen Rays; Simian virus 40; Solid; Source; Structure; Surface; Surface Plasmon Resonance; Synchrotrons; Testing; Therapeutic; Viral; Virion; Virus; Virus Receptors; Work; alpha-Defensins; base; carbohydrate receptor; design; extracellular; ganglioside receptor; improved; inhibitor/antagonist; molecular modeling; mouse polyomavirus; overexpression; particle; programs; receptor; research study; screening; serotonin receptor; small molecule; structural biology

The objective of this project is to elucidate mechanisms of attachment of human JCV. Attachment mechanisms of related polyomaviruses are known in atomic detail, and involve interactions between the viral capsid protein VPl and cell surface receptors that are ganghosides. Little is known about the molecular basis of JCV attachment. We have overexpressed the VPl capsid protein of JCV and obtained small crystals. An integrated research program is proposed to (i) determine high-resolution structures of the JCV capsid protein VPl in complex with oHgosaccharide receptors (ii) determine structures of the JCV capsid protein VPl in complex with relevant portions of the serotonin receptor 5HT2aR, and (iii) determine high-resolution structures of the JCV capsid protein VPl in complex with inhibitors. These aims should advance our understanding of JCV attachment to cells and point out strategies to intervene with the receptor interactions. As very few structure-function studies of virus-receptor interactions have been performed, the broader impact of this work will be in revealing general mechanisms by which pathogenic viruses recognize cellular receptors and cause organ-specific disease. We envision a high level of synergy between this project and projects 2 and 3, for the following reasons. The studies proposed here will provide a solid structural basis for understanding the binding modes of receptors and inhibitors to JCV, and this knowledge can then be directly used by the other projects to establish functional assays and to facilitate the development of effective small-molecule inhibitors. Vice versa, discoveries made by the other groups such as the identification of alpha-defensin as a JCV inhibtor can be directly used by us to provide a structural explanation for this interaction, which in turn can be used as platform for the development for other, strongly inhibitory ligands.

该项目的目的是阐明人类 JCV 的附着机制。的依附机制 相关的多瘤病毒的原子细节是已知的，并且涉及病毒衣壳蛋白之间的相互作用 VP1和细胞表面受体是神经节苷脂。关于 JCV 附着的分子基础知之甚少。 我们过表达了JCV的VP1衣壳蛋白并获得了小晶体。综合研究 提出程序是为了 (i) 确定 JCV 衣壳蛋白 VPl 与 低聚糖受体 (ii) 确定 JCV 衣壳蛋白 VPl 与相关复合物的结构 血清素受体 5HT2aR 的部分，以及 (iii) 确定 JCV 衣壳的高分辨率结构 与抑制剂形成复合物的蛋白质VP1。这些目标应能增进我们对 JCV 附着于细胞的理解 并指出干预受体相互作用的策略。由于很少有结构功能研究 病毒-受体相互作用已经进行，这项工作的更广泛影响将是揭示一般性 致病病毒识别细胞受体并引起器官特异性疾病的机制。我们 出于以下原因，预计该项目与项目 2 和 3 之间将产生高水平的协同作用。研究 这里提出的将为理解受体的结合模式提供坚实的结构基础 JCV 抑制剂，然后其他项目可以直接使用这些知识来建立功能 分析并促进有效小分子抑制剂的开发。反之亦然，发现 其他组，例如将α-防御素鉴定为JCV抑制剂，我们可以直接使用 为这种交互提供结构性解释，进而可以用作开发平台 对于其他强抑制性配体。