Is the HIV-1 capsid modulated by a pentamer switch?
Is the HIV-1 capsid modulated by a pentamer switch?
批准号:
10402590
负责人:
Barbie K. Ganser-Pornillos
金额:
$24.23万
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
项目状态:
已结题
起止时间:
2021-11-01 至 2023-10-31
关键词:
AIDS/HIV problemAdenovirusesAffinityAnimalsAntiviral AgentsArchitectureBehaviorBindingBinding SitesBiochemicalBiological ModelsCapsidComplexConeCoupledCouplesCryoelectron MicroscopyDNADataDevelopmentEnterovirusFullerenesFutureGenomeGeometryGlycineGoalsHIV-1In VitroIntegration Host FactorsLigand BindingLigandsModelingModernizationMolecularMolecular ConformationMutationNuclear PoreNuclear Pore Complex ProteinsNucleic AcidsPhenylalaninePhytic AcidPositioning AttributePropertyProteinsPublishingReagentReovirusReverse TranscriptionRoleRotavirusShapesSimplexvirusSite-Directed MutagenesisStructureSystemTechniquesTestingViralViral Reverse TranscriptionVirionVirusexperienceexperimental studyin vitro Modelinnovationmultimodal datanovelnovel therapeuticsparticlesmall moleculetripolyphosphateviral RNA
中文摘要
项目概要/摘要
HIV-1CA蛋白的12个五聚体具有塑造富勒烯锥几何形状的关键功能
在成熟的衣壳中,通过占据六角形衣壳晶格中的下倾或尖锐的曲率点,
从而允许组装的蛋白质壳闭合。除了这一结构性作用,
以前被归因于CA五聚体。在这里,我们提出了一个新的功能作用的艾滋病毒-1 CA
五聚体。我们的前提是,有两个不同的构象状态的五聚体,一个最初
通过体外组装系统鉴定,第二个观察到平均五聚体构型
在病毒体中。已发表的研究和我们的初步数据表明,这两种五聚体形式的区别在于:
两个配体结合位点的构型:一个为IP6,另一个为苯丙氨酸-甘氨酸(FG)
含有宿主蛋白如NUP153和其他核孔蛋白、CPSF6和SEC24C。我们建议
不同的五聚体状态定义了调节衣壳进入后结构的分子开关。我们
进一步提出,我们的五聚体开关假说可以解释理解不多的衣壳特性,
功能,如基础衣壳稳定性,脱壳和衣壳抑制的机制。在这
探索性R21项目,我们的主要目标是确定结构和生物化学性质的
提出了五聚体开关,并验证了构象转换与配体偶联的关键预测
约束力在两个特定目标中,我们将应用蛋白质热分析和cryoEM的现代实现,
在新的和建立的体外衣壳模型系统,范围从可溶性五聚体组装
captase样颗粒。如果得到证实,我们的新颖和创新的五聚体开关假设将大大扩展
了解HIV-1衣壳功能的分子基础,并可以为开发新的
靶向抗病毒药物
英文摘要
Project Summary/Abstract
Twelve pentamers of the HIV-1 CA protein have the critical function of shaping the fullerene cone geometry
of the mature capsid, by occupying declinations or sharp points of curvature in the hexagonal capsid lattice,
and thereby allowing the assembling protein shell to close. Apart from this structural role, no other function has
been previously ascribed to the CA pentamer. Here, we propose a novel functional role for the HIV-1 CA
pentamer. Our premise is that there are two distinct conformational states of the pentamer, one initially
identified through in vitro assembly systems and the second observed as the average pentamer configuration
in virions. Published studies and our preliminary data indicate that the two pentamer forms are distinguished by
the configurations of two ligand binding sites: one for IP6, and another for phenylalanine-glycine (FG)
containing host proteins such as NUP153 and other nucleoporins, CPSF6 and SEC24C. We propose that the
distinct pentamer states define a molecular switch that modulates the post-entry structure of the capsid. We
further propose that our pentamer switch hypothesis can explain poorly-understood capsid properties and
functions, such as mechanisms that underlie capsid stability, uncoating and capsid inhibition. In this
exploratory R21 project, our major goals are to define the structural and biochemical properties of the
proposed pentamer switch and test the key prediction that conformational switching is coupled to ligand
binding. In two Specific Aims, we will apply modern implementations of protein thermal profiling and cryoEM,
on novel and established in vitro capsid model systems that range from soluble pentamers to assembled
capsid-like particles. If proven, our novel and innovative pentamer switch hypothesis would significantly expand
understanding of the molecular basis of HIV-1 capsid function and could inform the development of novel
capsid-targeted antivirals.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Project 1. Maturation and Assembly
-
批准号:10653262
-
项目类别:
-
资助金额:$51.71万
-
财政年份:2022
-
负责人:Barbie K. Ganser-Pornillos
-
依托单位:
Project 1. Maturation and Assembly
-
批准号:10506952
-
项目类别:
-
资助金额:$48.51万
-
财政年份:2022
-
负责人:Barbie K. Ganser-Pornillos
-
依托单位:
Molecular mechanisms of the CA-SP1 switch in HIV assembly and maturation
-
批准号:10055953
-
项目类别:
-
资助金额:$45.19万
-
财政年份:2016
-
负责人:Barbie K. Ganser-Pornillos
-
依托单位:
Structure Analysis of Viral Assembly Mechanisms
-
批准号:8142303
-
项目类别:
-
资助金额:$40.28万
-
财政年份:2003
-
负责人:Barbie K. Ganser-Pornillos
-
依托单位:
Structure Analysis of Viral Assembly Mechanisms
-
批准号:8269842
-
项目类别:
-
资助金额:$40.4万
-
财政年份:2003
-
负责人:Barbie K. Ganser-Pornillos
-
依托单位:
Structure Analysis of Viral Assembly Mechanisms
-
批准号:8456141
-
项目类别:
-
资助金额:$38.99万
-
财政年份:2003
-
负责人:Barbie K. Ganser-Pornillos
-
依托单位:
海外基金