Structural understanding of the HIV-1 reverse transcription initiation process
HIV-1 逆转录起始过程的结构理解
基本信息
- 批准号:10675078
- 负责人:
- 金额:$ 59.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffinityArchitectureBindingBinding SitesBiological AssayBiologyComplexCryoelectron MicroscopyDNA biosynthesisDataDockingEnsureGenomeHIVHIV-1InvestigationLysine-Specific tRNAMedicineMichiganModelingMolecular ChaperonesMutation AnalysisNucleocapsidNucleocapsid ProteinsOutcomeProcessProductivityRNARNA-Directed DNA PolymeraseRegulationRepressionResolutionRetroviridaeReverse TranscriptionRoleSiteStructureSystemTestingTranscription InitiationTranscriptional RegulationTransfer RNAUniversitiesViralViral GenomeVirioninsightmutantreceptorstemstoichiometry
项目摘要
Abstract
In retroviruses, reverse transcription is initiated from an intermolecular duplex primer formed
by nucleocapsid-driven annealing of the U5-primer binding site (U5-PBS) region of the genome
with a host tRNA. However, the structure of this critical complex, and how reverse transcriptase
(RT) interacts with it is largely unknown. The structure of the HIV-1 complex presented in this
proposal shows that four tandem GNRA modules in U5-PBS spatially organizes the complex by
making continuous tetraloop-receptor docking interactions: one engages a rearranged tRNA, one
sequesters the initiation site, and two sequester the 18-bp primer to inhibit RT binding. Thus, in
contrast to the widely accepted model that a single RT molecule recognizes this complex to
initiate transcription, our data show that, in fact, two molecules of RT are required to bind in a
step-wise manner to release the repressed state and ensure accurate initiation: the first extensively
interacts with the U5 stem and acts as a remodeler, allowing for the subsequent one to bind the
canonical 18-bp primer and perform the enzymatic activity. Manipulation of the architecture, the
remodeling process, or competition with nucleocapsid, leads to severe loss of initiation accuracy.
Thus, this study redefines our basic understanding of HIV reverse transcription initiation; assigns
RT a structural remodeler role, separate from its enzymatic function; and indicates that the unique
mechanism may contribute to the control of start of DNA synthesis in virions. The aims will be:
(#1) to further detail the mechanism by mutational analysis, (#2) to understand the structural role
of NC and (#3) to determine the structures of the remodeler RT and enzymatic RT bound to the
U5-PBS:tRNAlys complex.
摘要
在逆转录病毒中,逆转录起始于形成的分子间双链体引物,
通过基因组的U 5-引物结合位点(U 5-PBS)区域的核衣壳驱动退火
与宿主tRNA结合然而,这个关键复合物的结构,以及逆转录酶如何
(RT)与它的相互作用在很大程度上是未知的。本文中介绍的HIV-1复合物的结构
该提案显示,U 5-PBS中的四个串联GNRA模块通过以下方式在空间上组织复合体:
进行连续的四环受体对接相互作用:一个与重排的tRNA结合,一个与重排的tRNA结合,
螯合起始位点,两个螯合18-bp引物以抑制RT结合。因此在
与广泛接受的模型相反,单个RT分子识别这种复合物,
启动转录,我们的数据表明,事实上,需要两个RT分子结合,
逐步的方式来释放压抑的状态,并确保准确的启动:第一个广泛的
与U 5茎相互作用并作为重塑剂,允许随后的一个结合U 5茎。
典型的18-bp引物,并进行酶活性。对建筑的操控,
重塑过程或与核衣壳的竞争导致严重的起始准确性损失。
因此,这项研究重新定义了我们对HIV逆转录起始的基本理解;
RT是一种结构重塑剂,与其酶功能分开;并表明,
该机制可能有助于控制病毒体中DNA合成的开始。其目标是:
(#1)通过突变分析进一步详细说明机制,(#2)了解结构作用
的NC和(#3)的结构,以确定与NC和(#3)结合的重塑RT和酶RT的结构。
U 5-PBS:tRNAlys复合物。
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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Victoria Manuel D'Souza其他文献
Victoria Manuel D'Souza的其他文献
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{{ truncateString('Victoria Manuel D'Souza', 18)}}的其他基金
Structural understanding of 7SK-snRNP mediated transcriptional regulation
7SK-snRNP 介导的转录调控的结构理解
- 批准号:
10583647 - 财政年份:2023
- 资助金额:
$ 59.79万 - 项目类别:
Structural understanding of the HIV-1 reverse transcription initiation process
HIV-1 逆转录起始过程的结构理解
- 批准号:
10547906 - 财政年份:2022
- 资助金额:
$ 59.79万 - 项目类别:
Joint Program in Molecules, Cells, and Organisms
分子、细胞和生物体联合项目
- 批准号:
10451816 - 财政年份:2020
- 资助金额:
$ 59.79万 - 项目类别:
Joint Program in Molecules, Cells, and Organisms
分子、细胞和生物体联合项目
- 批准号:
10620194 - 财政年份:2020
- 资助金额:
$ 59.79万 - 项目类别:
Joint Program in Molecules, Cells, and Organisms
分子、细胞和生物体联合项目
- 批准号:
10178050 - 财政年份:2020
- 资助金额:
$ 59.79万 - 项目类别:
Structure and Mechanism of Programmed Ribosomal Frameshifting in SARS coronavirus
SARS冠状病毒程序性核糖体移码的结构和机制
- 批准号:
8477378 - 财政年份:2013
- 资助金额:
$ 59.79万 - 项目类别:
Structure and Mechanism of Programmed Ribosomal Frameshifting in SARS coronavirus
SARS冠状病毒程序性核糖体移码的结构和机制
- 批准号:
8996115 - 财政年份:2013
- 资助金额:
$ 59.79万 - 项目类别:
Structure and Mechanism of Programmed Ribosomal Frameshifting in SARS coronavirus
SARS冠状病毒程序性核糖体移码的结构和机制
- 批准号:
8788944 - 财政年份:2013
- 资助金额:
$ 59.79万 - 项目类别:
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