RNA binding and packaging by retroviral Gag proteins
逆转录病毒 Gag 蛋白的 RNA 结合和包装
基本信息
- 批准号:10034983
- 负责人:
- 金额:$ 51.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-17 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:5&apos Untranslated RegionsAcylationAdoptedAffectBindingBinding SitesBiological AssayBiologyCell Culture TechniquesCellsCharacteristicsClinicalComputer ModelsDataDrug TargetingElementsEnsureFluorescence Resonance Energy TransferGenetic MaterialsHIV-1HeterogeneityHydroxyl RadicalIn VitroKineticsLabelMass Spectrum AnalysisMeasuresMediatingMolecular ConformationMutationNucleotidesPharmaceutical PreparationsPrimer ExtensionProductionPropertyRNARNA BindingRNA ConformationRNA ProbesRNA SplicingReportingRoleSpecificityStructureTestingTherapeuticTherapeutic AgentsTranscriptTranscription Initiation SiteViralViral GenomeVirionVirus AssemblyVirus ReplicationWorkZinc Fingersbasecostcrosslinkdesigndimerdimethyl sulfateexpectationfitnessgag Gene Productsgenomic RNAhammerhead ribozymeinhibitor/antagonistinsightmutantnovel strategiesnovel therapeuticsparticlepreferencepreventsingle moleculestoichiometrytargeted treatmentviral RNA
项目摘要
Abstract
HIV-1 packages two copies of genomic RNA (gRNA) as a dimer into newly formed viral particles. Retroviral
assembly doesn’t depend on the presence of gRNA, yet gRNA packaging is essential for production of infectious
virus particles. Robust and specific mechanisms must therefore be in place to ensure the genetic material is
passed on to progeny virions. While there are numerous therapeutics in clinical use, there are currently no gRNA
packaging or viral assembly inhibitors. Selective gRNA packaging is facilitated by interactions between the HIV-
1 Gag protein and conserved gRNA elements within the 5′ untranslated region (5′UTR). Here, we focus on recent
unexpected findings in HIV-1 RNA biology that revealed sequence heterogeneity at the 5′ end of the HIV-1 RNA
transcript. The variable number of G residues (1G, 2G and 3G) has been reported to affect the gRNA localization,
with 1G RNA preferentially selected over 3G to be the viral genome. This is very surprising given that these two
9-kb RNAs only differ by 2 nucleotides. Preliminary data presented here strongly support the enrichment of 1G-
containing transcripts among packaged gRNA. Importantly, various point mutants that abrogate the preference
for 1G RNA have been identified. Exciting preliminary data support our major hypothesis that the ensemble of
RNA structures adopted by the 5′UTR is significantly altered in 1G vs. 3G transcripts. These data provide a
strong starting point for the proposed studies aimed at elucidating the mechanism by which transcriptional start
site choice modulates gRNA packaging selectivity. More broadly, we will gain insights into how subtle sequence
changes can alter the ensemble of 5′UTR RNA structures and impact viral replication fitness. The specific aims
are: (1) To probe wild-type and mutant retroviral gRNA structure and dynamics; (2) To probe wild-type and
mutant HIV-1 Gag RNA binding and packaging specificity. The results of these studies will help guide the design
of novel therapeutic agents that target the 5′UTR and interfere with the essential conformational plasticity and/or
key binding interactions with the expectation for a lower rate of mutational escape than conventional drugs.
摘要
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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Karin M Musier-Forsyth其他文献
Karin M Musier-Forsyth的其他文献
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{{ truncateString('Karin M Musier-Forsyth', 18)}}的其他基金
Mechanism of selective packaging of primer tRNALys3 by HIV-1
HIV-1选择性包装引物tRNALys3的机制
- 批准号:
10258167 - 财政年份:2021
- 资助金额:
$ 51.53万 - 项目类别:
Translational quality control by trans-editing domains
通过转编辑域控制翻译质量
- 批准号:
10206957 - 财政年份:2021
- 资助金额:
$ 51.53万 - 项目类别:
Mechanism of selective packaging of primer tRNALys3 by HIV-1
HIV-1选择性包装引物tRNALys3的机制
- 批准号:
10376353 - 财政年份:2021
- 资助金额:
$ 51.53万 - 项目类别:
Translational quality control by trans-editing domains
通过转编辑域控制翻译质量
- 批准号:
10406288 - 财政年份:2021
- 资助金额:
$ 51.53万 - 项目类别:
Translational quality control by trans-editing domains
通过转编辑域控制翻译质量
- 批准号:
10605294 - 财政年份:2021
- 资助金额:
$ 51.53万 - 项目类别:
Translational quality control by trans-editing domains
通过转编辑域控制翻译质量
- 批准号:
10822416 - 财政年份:2021
- 资助金额:
$ 51.53万 - 项目类别:
Translational quality control by trans-editing domains
通过转编辑域控制翻译质量
- 批准号:
10580273 - 财政年份:2021
- 资助金额:
$ 51.53万 - 项目类别:
RNA binding and packaging by retroviral Gag proteins
逆转录病毒 Gag 蛋白的 RNA 结合和包装
- 批准号:
10576298 - 财政年份:2020
- 资助金额:
$ 51.53万 - 项目类别:
RNA binding and packaging by retroviral Gag proteins
逆转录病毒 Gag 蛋白的 RNA 结合和包装
- 批准号:
10347332 - 财政年份:2020
- 资助金额:
$ 51.53万 - 项目类别:
Cellular Factors Critical for Initiation of HIV-1 Reverse Transcriptase
对 HIV-1 逆转录酶启动至关重要的细胞因素
- 批准号:
10393691 - 财政年份:2014
- 资助金额:
$ 51.53万 - 项目类别:
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