Structural basis of vesucular stomatitis virus transcription and replication
水疱性口炎病毒转录和复制的结构基础
基本信息
- 批准号:8711998
- 负责人:
- 金额:$ 34.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-09 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectBase SequenceBinding SitesBiochemical GeneticsBiological AssayComplementComplexDockingElectron MicroscopyEngineeringFamilyGenesGenetic TranscriptionGenomicsGlycine decarboxylaseGoalsImageIndividualInfectionMethodologyMethodsMutationNucleocapsidNucleocapsid ProteinsPhenotypePhosphoproteinsPlayPoly APolymerasePolynucleotidesProcessProtein BindingProtein Binding DomainProtein FragmentProteinsRNARNA ConformationRNA SequencesRNA VirusesRNA chemical synthesisRNA-Directed RNA PolymeraseResolutionRoleSeriesSiteStomatitisStructureTechniquesTranscription InitiationTranscriptional RegulationVesicular stomatitis Indiana virusViralViral ProteinsVirusX-Ray Crystallographybaseinterestmutantnovelparticlepositional cloningreplicaseresearch studyvesicular stomatitis virus L proteinviral RNA
项目摘要
DESCRIPTION (provided by applicant): Negative strand RNA viruses (NRVs), such as vesicular stomatitis virus (VSV), are unique because their nucleocapsid, not the naked RNA, is the active template for transcription and replication. During the complete infection cycle, the genomic RNA is completely sequestered by the nucleocapsid protein (N). The viral RNA-dependent RNA polymerase (RdRp, a complex between L and P) must gain access to the bases of the RNA in order to initiate transcription or replication. Our previous structural studies
showed how the RNA is encapsidated by the nucleocapsid, as well as the structure and accessibility of the RNA within the encapsidation cavity. Since the nucleocapsid is the template for viral RNA synthesis and given the intimate association between N and the RNA, questions arise as to what role the N protein may play in transcription and replication. The new studies proposed here are focused on: Aim 1, the structural requirement of the functional template in initiation of viral transcription and replication. We have developed methods to solve the structure
of specific RNA sequences encapsidated within nucleocapsid-like particles (NLPs). In this aim, we plan to solve a novel series of structures aimed toward addressing the question about how the N protein helps RdRp to recognize specific RNA sequences sequestered in the nucleocapsid. This will be complemented with a look at structural changes in the N protein that affect transcription/replication. This will be accomplished by studying a series of mutant N proteins with phenotypes that affect these enzymatic processes. These mutants suggest that the N protein itself plays a role in regulation of transcription/replication. In Aim 2, we will examine polynucleotide synthesis from the role of the L and P proteins, rather than the functional template. We have engineered a series of L protein fragments that are soluble, two of which have been crystallized. We will determine structures for several domains of L. These will be integrated with EM studies of the L, P and N proteins aimed at reconstructing the larger tripartite replicase complex. Collectively, the studies proposed here will address both replication
and transcription from two perspectives, the template as well as the machinery involved in this critical enzymatic process.
描述(由申请方提供):负链RNA病毒(NRV),如水泡性口炎病毒(VSV),是独特的,因为它们的核衣壳,而不是裸RNA,是转录和复制的活性模板。在整个感染周期中,基因组RNA完全被核衣壳蛋白(N)隔离。病毒RNA依赖性RNA聚合酶(RdRp,L和P之间的复合物)必须接近RNA的碱基,以启动转录或复制。我们之前的结构研究
显示了RNA是如何被核衣壳包裹的,以及RNA在包裹腔内的结构和可及性。由于核衣壳是病毒RNA合成的模板,并且考虑到N和RNA之间的密切联系,因此出现了N蛋白在转录和复制中可能发挥什么作用的问题。本文提出的新的研究集中在:目的1,在启动病毒转录和复制的功能模板的结构要求。我们已经开发出解决结构的方法
核衣壳样颗粒(NLP)内的特异性RNA序列。在这个目标中,我们计划解决一系列新的结构,旨在解决有关N蛋白如何帮助RdRp识别核衣壳中隔离的特定RNA序列的问题。这将是补充看看在N蛋白的结构变化,影响转录/复制。这将通过研究一系列具有影响这些酶促过程的表型的突变N蛋白来实现。这些突变体表明N蛋白本身在转录/复制的调节中起作用。在目标2中,我们将从L和P蛋白的作用而不是功能模板来研究多核苷酸合成。我们已经设计了一系列可溶的L蛋白片段,其中两个已经结晶。我们将确定L的几个域的结构。这些将与EM研究的L,P和N蛋白,旨在重建更大的三方复制酶复合物。总的来说,这里提出的研究将解决复制
和转录从两个角度来看,模板以及在这一关键的酶促过程中所涉及的机制。
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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Todd Jason Green其他文献
Todd Jason Green的其他文献
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{{ truncateString('Todd Jason Green', 18)}}的其他基金
Pathogenic Autoantibodies with Specificity for Aberrant Glycoproteins: Assessment of a Therapeutic Target in an Autoimmune Disease
具有异常糖蛋白特异性的致病性自身抗体:自身免疫性疾病治疗靶点的评估
- 批准号:
10581585 - 财政年份:2020
- 资助金额:
$ 34.43万 - 项目类别:
Pathogenic Autoantibodies with Specificity for Aberrant Glycoproteins: Assessment of a Therapeutic Target in an Autoimmune Disease
具有异常糖蛋白特异性的致病性自身抗体:自身免疫性疾病治疗靶点的评估
- 批准号:
10359090 - 财政年份:2020
- 资助金额:
$ 34.43万 - 项目类别:
Pathogenic Autoantibodies with Specificity for Aberrant Glycoproteins: Assessment of a Therapeutic Target in an Autoimmune Disease
具有异常糖蛋白特异性的致病性自身抗体:自身免疫性疾病治疗靶点的评估
- 批准号:
10117072 - 财政年份:2020
- 资助金额:
$ 34.43万 - 项目类别:
Transcription and replication in nonsegmented negative-strand RNA viruses
非节段负链RNA病毒的转录和复制
- 批准号:
9195690 - 财政年份:2015
- 资助金额:
$ 34.43万 - 项目类别:
Transcription and replication in nonsegmented negative-strand RNA viruses
非节段负链RNA病毒的转录和复制
- 批准号:
8991460 - 财政年份:2015
- 资助金额:
$ 34.43万 - 项目类别:
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