Structure and function of the portal vertex on the herpes simplex virus capsid
单纯疱疹病毒衣壳汇管顶点的结构和功能
基本信息
- 批准号:10592314
- 负责人:
- 金额:$ 65.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:ArchitectureBindingBiochemicalCapsidCell SeparationComplexCryoelectron MicroscopyDNA PackagingDataDefectDevelopmentGenesGeneticGenomeHerpesviridaeHerpesviridae InfectionsHerpesvirus 1ImageIn SituInfectionInfection preventionKnowledgeLaboratoriesLengthMorphologyPositioning AttributeProcessProteinsPublishingReactionResearchRoleSimplexvirusSiteStructureTechniquesTestingTherapeuticTherapeutic EffectViralViral GenesViral GenomeViral PackagingViral ProteinsVirionVirusVirus ReplicationVisualizationadenovirus penton proteindensitydesignhuman pathogeninnovationinsightmutantpreventprotein functionreconstructionrecruitstructural biologyterminaseviral DNAvirology
项目摘要
ABSTRACT
This project aims to elucidate the interactions of the herpes simplex virus portal vertex with
replicated viral DNA and the HSV packaging machinery. The packaging and cleavage of
replicated viral DNA into preformed capsids is a critical step during herpesvirus infection. For
herpes simplex virus type 1 (HSV-1), this process requires the products of seven viral genes:
UL6, UL15, UL17, UL25, UL28, UL32, and UL33. Most of the proteins involved in capsid assembly
and DNA packaging are conserved suggesting that these mechanisms will also be similar for all
herpesviruses. The proposed research by the Homa and[CJF1] Conway laboratories combines
expertise in virology and structural biology for determining the interaction of the
cleavage/packaging proteins with the capsid portal vertex leading to stable packaging of a unit
length genome. Understanding the herpesvirus portal structure and its interaction with the
packaging machinery has been hampered due to the subtle morphological differences between
the portal and penton vertices. However, recent advances in cryoEM techniques have allowed
portals to be localized in images of intact capsids yielding important structural information about
the portal and associated proteins. The pUL6 portal dodecamer appears to be anchored to the
capsid by interactions with the peri-pentonal triplexes as well as helical density attributed to the
pUL17 and pUL25 subunits of the capsid vertex specific component (CVSC). Here we propose
combined biochemical and structural studies focusing on the unique portal vertex of wild type
HSV and packaging mutants that will provide insights into the mechanism of HSV genome
packaging. We aim to understand the functions of the CVSC components, their interactions with
the portal vertex and with the terminase complex in cleavage and retention of the packaged viral
genome. Based on published and preliminary studies, we believe the pUL17 is emerging as a key
player in capsid assembly and maturation. We hypothesize that pUL17 anchors the terminase
complex to the portal and, after packaging is complete, recruits pUL25 to the portal to retain the
viral genome. We will test the hypothesis in two specific Aims that together investigate the
structure and function of the portal vertex. Aim 1 focuses on the viral proteins required for the
portal complex to interact with the replicated viral genome and initiate the cleavage packaging
reaction. Aim 2 follows a complementary structural approach to understand the architecture of
the portal vertex, include the components required for different stages of assembly and
packaging. Our results will inform the development of innovative and specific therapeutics
designed to prevent herpesvirus replication by blocking DNA packaging.
摘要
该项目旨在阐明单纯疱疹病毒门脉顶点与
复制病毒DNA和HSV包装机械。蛋白质的包装和切割
将病毒DNA复制到预先形成的衣壳中是疱疹病毒感染过程中的关键步骤。为
单纯疱疹病毒1型(HSV-1),这一过程需要七种病毒基因的产物:
UL6、UL15、UL17、UL25、UL28、UL32和UL33。大多数参与衣壳组装的蛋白质
DNA包装是保守的,这表明这些机制对所有人来说也将是相似的
疱疹病毒。霍马实验室和[CJF1]康威实验室拟议的研究结合
病毒学和结构生物学方面的专门知识,用于确定病毒的相互作用
具有衣壳入口顶点的切割/包装蛋白质导致单位的稳定包装
长度基因组。了解疱疹病毒门户结构及其与病毒的相互作用
包装机械一直受到阻碍,因为它们之间的细微形态差异
门户和五角星顶点。然而,低温电磁技术的最新进展使
门户将在完整衣壳的图像中定位,从而产生关于
门户及相关蛋白。PUL6门户十二聚体似乎锚定在
衣壳与周五角形三联体的相互作用以及归因于
衣壳顶点特定成分(CVSC)的pUL17和pUL25亚基。在这里,我们建议
野生型独特门脉顶端的生化与结构相结合的研究
HSV和包装突变体将为深入了解HSV基因组的机制提供帮助
包装。我们的目标是了解CVSC组件的功能、它们与
门静脉顶端和末端酶复合体对包装病毒的切割和滞留
基因组。根据已发表的和初步的研究,我们认为pUL17正在成为一个关键
球员在衣帽的组装和成熟。我们假设pUL17锚定了末端酶
复杂到门户,在打包完成后,将pUL25招募到门户以保留
病毒基因组。我们将在两个特定目标中测试该假设,这两个目标一起调查
门户顶点的结构和功能。目标1集中在病毒所需的蛋白质上
与复制的病毒基因组相互作用并启动切割包装的门户复合体
反应。目标2遵循补充的结构方法来理解
门户顶点,包括组装的不同阶段所需的组件
包装。我们的结果将为创新和特定疗法的发展提供信息
旨在通过阻止DNA包装来防止疱疹病毒复制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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James F. Conway其他文献
The making and breaking of symmetry in virus capsid assembly: glimpses of capsid biology from cryoelectron microscopy
病毒衣壳组装中对称性的形成和破坏:从冷冻电子显微镜观察衣壳生物学
- DOI:
10.1096/fasebj.11.10.9271358 - 发表时间:
1997 - 期刊:
- 影响因子:0
- 作者:
A. Steven;B. Trus;F. Booy;N. Cheng;A. Zlotnick;J. Castón;James F. Conway - 通讯作者:
James F. Conway
Filamentous hemagglutinin of Bordetella pertussis. A bacterial adhesin formed as a 50-nm monomeric rigid rod based on a 19-residue repeat motif rich in beta strands and turns.
百日咳博德特氏菌的丝状血凝素。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:5.6
- 作者:
A. Makhov;J. H. Hannah;M. Brennan;B. Trus;Eva Kocsis;James F. Conway;P. Wingfield;Martha N. Simon;A. Steven - 通讯作者:
A. Steven
Digital image processing of electron micrographs: the PIC system-III.
电子显微照片的数字图像处理:PIC 系统-III。
- DOI:
10.1006/jsbi.1996.0011 - 发表时间:
1996 - 期刊:
- 影响因子:3
- 作者:
B. Trus;Eva Kocsis;James F. Conway;A. Steven - 通讯作者:
A. Steven
Structural basis of deoxynucleotide addition by HIV-1 RT during reverse transcription
HIV-1 RT 在逆转录过程中添加脱氧核苷酸的结构基础
- DOI:
10.1038/s41467-024-54618-y - 发表时间:
2024-12-04 - 期刊:
- 影响因子:15.700
- 作者:
Sandra Vergara;Xiaohong Zhou;Ulises Santiago;Mounia Alaoui-El-Azher;James F. Conway;Nicolas Sluis-Cremer;Guillermo Calero - 通讯作者:
Guillermo Calero
Cysteine Mapping of Cytoplasmic Dynein Motor Domain
- DOI:
10.1016/j.bpj.2009.12.3979 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Hikmat N. Daghestani;James F. Conway;Billy W. Day - 通讯作者:
Billy W. Day
James F. Conway的其他文献
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{{ truncateString('James F. Conway', 18)}}的其他基金
Structure and assembly of dsDNA tailed bacteriophages
双链 DNA 尾噬菌体的结构和组装
- 批准号:
10708742 - 财政年份:2022
- 资助金额:
$ 65.25万 - 项目类别:
Structure and assembly of dsDNA tailed bacteriophages
双链 DNA 尾噬菌体的结构和组装
- 批准号:
10382154 - 财政年份:2022
- 资助金额:
$ 65.25万 - 项目类别:
Structure and function of the portal vertex on the herpes simplex virus capsid
单纯疱疹病毒衣壳汇管顶点的结构和功能
- 批准号:
10393649 - 财政年份:2021
- 资助金额:
$ 65.25万 - 项目类别:
Structure and Function of the Herpesvirus Capsid and its DNA-Packaging Machinery
疱疹病毒衣壳及其 DNA 包装机制的结构和功能
- 批准号:
8501312 - 财政年份:2011
- 资助金额:
$ 65.25万 - 项目类别:
Structure and Function of the Herpesvirus Capsid and its DNA-Packaging Machinery
疱疹病毒衣壳及其 DNA 包装机制的结构和功能
- 批准号:
8695282 - 财政年份:2011
- 资助金额:
$ 65.25万 - 项目类别:
Training in Molecular Biophysics and Structural Biology
分子生物物理学和结构生物学培训
- 批准号:
9305776 - 财政年份:2011
- 资助金额:
$ 65.25万 - 项目类别:
Structure and Function of the Herpesvirus Capsid and its DNA-Packaging Machinery
疱疹病毒衣壳及其 DNA 包装机制的结构和功能
- 批准号:
8104603 - 财政年份:2011
- 资助金额:
$ 65.25万 - 项目类别:
Structure and Function of the Herpesvirus Capsid
疱疹病毒衣壳的结构和功能
- 批准号:
9089794 - 财政年份:2011
- 资助金额:
$ 65.25万 - 项目类别:
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