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。附件机制 相关的多瘤病毒在原子细节上是已知的，并且涉及病毒衣壳蛋白之间的相互作用 VP 1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。 我们已经过表达了JCV的VP 1衣壳蛋白，并获得了小晶体。综合研究 提出了一个程序来（i）确定与以下物质复合的JCV衣壳蛋白VP 1的高分辨率结构： （ii）α-H糖受体决定与相关的α-H糖受体复合的JCV衣壳蛋白VP 1的结构。 5-羟色胺受体5 HT 2aR的部分，和（iii）确定JCV衣壳的高分辨率结构 与抑制剂复合的蛋白VP 1。这些目标将促进我们对JCV附着于细胞的理解 并指出干预受体相互作用的策略。因为很少有结构-功能研究 病毒-受体相互作用已经进行，这项工作的更广泛的影响将是揭示一般 致病病毒识别细胞受体并导致器官特异性疾病的机制。我们 设想本项目与项目2和项目3之间高度协同，原因如下。研究 本文提出的方法将为理解受体的结合模式提供坚实的结构基础， JCV的抑制剂，然后这些知识可以直接用于其他项目，以建立功能性 分析和促进有效的小分子抑制剂的开发。反之亦然， 其他组，例如鉴定α-防御素为JCV抑制剂，可直接用于 为这种相互作用提供了一个结构性的解释，这反过来又可以用作开发的平台。 对于其他强抑制配体。