Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
HIV-1 Env 刺突膜相互作用域的结构功能研究
基本信息
- 批准号:9203214
- 负责人:
- 金额:$ 85.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-05-20 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:AdoptedAlanineAntigensArginineBindingBiochemistryBiogenesisBiological AssayC-terminalCCR5 geneCD4 AntigensCXCR4 geneCell fusionCell membraneCell surfaceCellsChargeCleaved cellClinical ResearchComputer SimulationCouplingCrystallographyCytoplasmic TailDataDevelopmentElementsEnvironmentEpitopesEventGoalsHIVHIV Envelope Protein gp120HIV-1HIV-1 vaccineHIV-2InfectionKnowledgeLeadLipid BilayersLipidsLysineMediatingMembraneMembrane FusionMolecular ConformationMutagenesisMutationPeptidesPlayProductionPropertyProtein EngineeringProteinsResolutionRoleSIVScanningSideStructureSurfaceTechnologyTestingTransmembrane DomainViralVirionVirus AssemblyVirus Diseasesbasedesignenv Glycoproteinsgp160insightlarge scale productionnanodiskneutralizing antibodynovelreceptorreconstitutionstructural biologyvaccine development
项目摘要
Project Summary
The first critical step of HIV-1 infection is fusion of viral and target cell membranes mediated by envelope
glycoprotein (Env). The mature Env spikes [trimeric (gp160)3, cleaved to (gp120/gp41)3] are the sole antigens
on the virion surface. Conformational changes in gp120 when triggered by binding to receptor (CD4) and co-
receptor (e.g., CCR5 or CXCR4) lead to a cascade of refolding events in gp41, and ultimately to membrane
fusion. Vast amount of structural information is available for the ectodomain of Env, but much less is known
regarding its transmembrane domain (TMD) and its membrane-proximal (MP) regions, including the membrane
proximal external region (MPER) and the cytoplasmic tail (CT). We recently made an unexpected discovery
that truncation of the CT domain drastically reshapes the antigenic surfaces of the Env ectodomain on the
other side of the membrane. Deep understanding of the physical coupling (conformation and/or dynamics)
between the CT and the ectodomain mediated by the TMD may guide Env-based immunogen design to induce
broadly neutralizing antibodies (bnNabs). We thus hypothesize that the membrane-interacting domains
(MPER, TMD and CT) of HIV-1 Env adopt defined structures which are critical for its stability, function
and antigenicity. We have already completed a TMD structure at the atomic resolution using the state-of-the-
art NMR technology. When reconstituted in bicelles that mimic lipid bilayer, the TMD forms a well-ordered
trimer mainly stabilized by a tightly packed hydrophilic core near its C-terminal end that can potentially be
influenced by the CT domain. In this application, we plan to combine structural biology approaches and
functional assays to elucidate the roles of the membrane-interacting domains of HIV-1 Env. We will purse the
following specific aims: 1) we will investigate TMD assembly of HIV and SIV Env and possible interaction with
the fusion peptide; 2) we will provide structural information for the MP regions of Env in the context of
membrane; 3) we will elucidate the role of the membrane-interacting domains of Env in its stability, function
and antigenicity; 4) we will design trimer immunogens to mimic the native and functional HIV-1 Env spike..
项目摘要
HIV-1感染的第一个关键步骤是通过包膜介导的病毒和靶细胞膜的融合
糖蛋白(Env)。成熟的Env棘突[三聚体(Gp160)3,裂解为(gp120/gp41)3]是唯一的抗原
在病毒粒子表面。Gp120与受体结合时的构象变化
受体(如CCR5或CXCR4)导致gp41中一系列的折叠事件,最终导致膜
核聚变。Env的外域有大量的结构信息,但我们知道的要少得多
关于其跨膜结构域(TMD)及其膜近端(MP)区域,包括膜
近端外区(MPER)和胞浆尾部(CT)。我们最近有了一个意想不到的发现
CT域的截断极大地重塑了包膜外区的抗原性表面
膜的另一边。对物理耦合(构象和/或动力学)有深入的了解
TMD介导的CT和胞外区之间的关系可能指导基于Env的免疫原设计
广谱中和抗体(BnNAb)。因此我们假设,膜相互作用的区域
HIV-1环境蛋白(MPER、TMD和CT)采用特定的结构,这些结构对其稳定性、功能至关重要
和抗原性。我们已经完成了原子分辨率的TMD结构,使用的是状态-
ART核磁共振技术。当TMD在模拟脂质双层的双分子中重组时,TMD形成有序的
三聚体主要由其C-末端附近紧密堆积的亲水性核心稳定,该核心可能是
受CT域的影响。在这项应用中,我们计划将结构生物学方法和
功能分析以阐明HIV-1env膜相互作用结构域的作用。我们会把钱花在
具体目标如下:1)我们将研究HIV和SIV Env的TMD组装以及可能的相互作用
2)我们将在以下背景下提供Env的MP区域的结构信息
我们将阐明env的膜相互作用结构域在其稳定性、功能中的作用。
和抗原性;4)我们将设计三聚体免疫原来模拟天然的和功能强大的HIV-1环境蛋白尖峰。
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 Jeiwen CHOU其他文献
JAMES Jeiwen CHOU的其他文献
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{{ truncateString('JAMES Jeiwen CHOU', 18)}}的其他基金
Structural and Functional Roles of the Membrane-Related Components of Single-Pass Membrane Proteins
单程膜蛋白膜相关成分的结构和功能作用
- 批准号:
10380877 - 财政年份:2021
- 资助金额:
$ 85.83万 - 项目类别:
CONTROL AND ACTIVATION OF THE TUMOR NECROSIS FACTOR RECEPTORS
肿瘤坏死因子受体的控制和激活
- 批准号:
10338106 - 财政年份:2020
- 资助金额:
$ 85.83万 - 项目类别:
CONTROL AND ACTIVATION OF THE TUMOR NECROSIS FACTOR RECEPTORS
肿瘤坏死因子受体的控制和激活
- 批准号:
10092951 - 财政年份:2020
- 资助金额:
$ 85.83万 - 项目类别:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
HIV-1 Env 刺突膜相互作用域的结构功能研究
- 批准号:
10326632 - 财政年份:2016
- 资助金额:
$ 85.83万 - 项目类别:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
HIV-1 Env 刺突膜相互作用域的结构功能研究
- 批准号:
9275921 - 财政年份:2016
- 资助金额:
$ 85.83万 - 项目类别:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
HIV-1 Env 刺突膜相互作用域的结构功能研究
- 批准号:
9899171 - 财政年份:2016
- 资助金额:
$ 85.83万 - 项目类别:
Function and mechanism of the HCV p7 channel and its therapeutic potential
HCV p7通道的功能、机制及其治疗潜力
- 批准号:
9198039 - 财政年份:2016
- 资助金额:
$ 85.83万 - 项目类别:
Function and mechanism of the HCV p7 channel and its therapeutic potential
HCV p7通道的功能、机制及其治疗潜力
- 批准号:
8880443 - 财政年份:2014
- 资助金额:
$ 85.83万 - 项目类别:
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