STRUCTURAL BIOLOGY OF JCV HOST CELL RECOGNITION

JCV宿主细胞识别的结构生物学

• 批准号: 8304287
• 负责人: THILO STEHLE
• 金额: $ 18.07万
• 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/8304287
• 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; Screening procedure; 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; 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.

本项目的目的是阐明人JCV的附着机制。的依附机制 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 VPL和细胞表面受体是神经节苷脂。人们对JCV附着的分子基础知之甚少。 我们过表达了JCV的VPL衣壳蛋白，并获得了较小的晶体。综合研究 程序被用来(I)确定JCV衣壳蛋白VPL的高分辨结构 OHGR(II)决定JCV衣壳蛋白VPL的结构 5-羟色胺受体5HT2AR的一部分，以及(Iii)确定JCV衣壳的高分辨率结构 蛋白VPL与抑制剂形成复合体。这些目标应该会促进我们对JCV附着于细胞的理解 并指出了干预受体相互作用的策略。由于对其结构和功能的研究很少 病毒-受体相互作用已经完成，这项工作的更广泛影响将在揭示一般 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，可以设想该项目与项目2和3之间的高度协同作用。这些研究 为理解受体和受体的结合方式提供了坚实的结构基础 JCV的抑制因素，这些知识然后可以直接被其他项目用来建立功能 测试和促进有效的小分子抑制剂的开发。反之亦然 其他组，如α-防御素作为JCV抑制物的鉴定，可以直接用于我们 为这种交互提供结构化的解释，这反过来又可以用作开发的平台 对于其他具有强烈抑制作用的配体。