Structure of HIV-1 envelope spike in the context of membrane
膜背景下 HIV-1 包膜刺突的结构
基本信息
- 批准号:10538590
- 负责人:
- 金额:$ 53.1万
- 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:2020-01-16 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdoptedAntibodiesAntigensBindingBiochemicalCCR5 geneCD4 AntigensCXCR4 geneCellsComplexCryoelectron MicroscopyCytoplasmic ProteinCytoplasmic TailEnvironmentGeneticGenetic VariationGlycoproteinsGoalsHIVHIV Envelope Protein gp120HIV-1HIV-1 vaccineInfectionLeadLengthLipid BilayersLipidsMediatingMembraneMembrane FusionMembrane ProteinsMolecularMolecular ConformationPlayProbabilityProcessProteinsProtocols documentationReportingResistanceResolutionRoleSamplingSeriesStructureTechnologyTransmembrane DomainVaccine DesignVariantViralVirusVisualizationchemokine receptorenv Gene Productsgag Gene Productsgp160matrix protein, Human immunodeficiency virus type 1nanodisc technologynanodisknovelparticleprotein reconstitutionprotein structurereceptorreceptor bindingreconstitutionstructural biologyvaccine development
项目摘要
Project Summary
Membrane fusion, mediated by HIV-1 envelope glycoprotein [Env; trimeric (gp160)3 cleaved to (gp120/gp41)3],
is the first critical step for the virus to enter host cells and establish infection. A mature Env spike contains
three copies each of noncovalently-associated receptor-binding subunit gp120 and fusion subunit gp41. A
general picture of viral membrane fusion has emerged from extensive biochemical and structural studies.
Sequential binding of gp120 to the primary receptor CD4 and a coreceptor leads to large, irreversible structural
rearrangements in gp41, which drive the membrane fusion process. Despite tremendous progress in our
understanding of the structure of HIV-1 Env over the last two decades, largely based on studies of its soluble
fragments, we still lack an atomic picture of the full-length Env in a membrane environment. In a series of
recent studies, we have determined the structures of the transmembrane domain, membrane proximal external
region, as well as a portion of the cytoplasmic tail of HIV-1 Env in bicelles that mimic lipid bilayers by NMR.
Unexpectedly, we find that these regions all form well-ordered trimeric clusters in the presence of a lipid bilayer
and that disruption of any of them reduces membrane fusion efficiency and alters the antigenic structure of the
entire Env, suggesting that they play critical structural and functional roles. These new findings provide a
strong scientific premise to determine the structure of the full-length HIV-1 Env reconstituted in lipid
nanodiscs by cryo-electron microscopy (cryoEM). We hypothesize that the transmembrane and membrane-
proximal regions of HIV-1 Env all adopt defined oligomeric structures that are critical for the stability,
function and antigenicity of the full-length protein in membrane. We will capitalize on the recent advances
in cryoEM and nanodisc technology and plan to determine structures of the full-length Env proteins,
reconstituted in lipid bilayers, both alone or in complex with the matrix protein. Our goal is to visualize novel
structural features of the intact Env proteins in the context of membrane, to gain a full understanding of their
structure-function and to facilitate Env-based immunogen design for vaccine development. We will purse the
following specific aims: 1) we will determine the structure of a full-length HIV-1 Env in the context of
membrane, 2) we will determine the structural basis for antigenic differences of the intact Env in membrane
among HIV-1 isolates with different antibody sensitivity, and 3) we will determine the structure of a full-length
HIV-1 Env in complex with matrix protein.
项目摘要
膜融合,由HIV-1包膜糖蛋白[env;三聚体(Gp160)3裂解为(gp120/gp41)3],
是病毒进入宿主细胞并建立感染的第一个关键步骤。一个成熟的环境尖刺包含
非共价结合受体结合亚基gp120和融合亚基gp41各三个拷贝。一个
广泛的生化和结构研究揭示了病毒膜融合的概貌。
Gp120与主要受体cd4和辅助受体的顺序结合导致大的、不可逆的结构。
Gp41中的重排,这驱动了膜融合过程。尽管我们在这方面取得了巨大进步
近二十年来对HIV-1env结构的了解,主要是基于对其可溶性的研究
我们仍然缺乏膜环境中全长Env的原子图像。在一系列
最近的研究,我们已经确定了跨膜区的结构,膜近端的外部
区域,以及HIV-1Env胞质尾部的一部分,用核磁共振技术模拟脂质双层。
出乎意料的是,我们发现这些区域都在脂双层的存在下形成了有序的三聚体簇合物
而其中任何一种的破坏都会降低膜融合效率并改变病毒的抗原结构
整个环境,表明它们在结构和功能上发挥着关键作用。这些新的发现提供了一个
确定脂类重组HIV-1全长包膜结构的有力科学前提
纳米盘的冷冻电子显微镜(CryoEM)。我们假设跨膜和膜-
HIV-1Env的近端区域都采用对稳定性至关重要的确定的寡聚结构,
膜全长蛋白的功能和抗原性。我们将充分利用最近的进展。
在低温电子显微镜和纳米盘技术中,并计划确定全长环境蛋白的结构,
在脂双层中重组,单独或与基质蛋白形成复合体。我们的目标是将小说形象化
膜环境下完整的Env蛋白的结构特征,以获得对其
结构-功能,并促进基于包膜病毒的免疫原设计,用于疫苗开发。我们会把钱花在
以下是具体目标:1)我们将在以下背景下确定全长HIV-1环境病毒的结构
膜,2)我们将确定膜上完整包膜抗原差异的结构基础
在抗体敏感性不同的HIV-1分离株中,以及3)我们将确定全长结构
HIV-1包膜蛋白与基质蛋白形成复合体。
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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Bing Chen其他文献
Bing Chen的其他文献
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{{ truncateString('Bing Chen', 18)}}的其他基金
Exploring the membrane-related components of HIV-1 Env for immunogen design
探索 HIV-1 Env 的膜相关成分以进行免疫原设计
- 批准号:
10762577 - 财政年份:2023
- 资助金额:
$ 53.1万 - 项目类别:
Structure of HIV-1 envelope spike in the context of membrane
膜背景下 HIV-1 包膜刺突的结构
- 批准号:
10322988 - 财政年份:2020
- 资助金额:
$ 53.1万 - 项目类别:
Structure of the full-length spike protein of SARS-CoV-2 in the context of membrane
膜背景下 SARS-CoV-2 全长刺突蛋白的结构
- 批准号:
10117733 - 财政年份:2020
- 资助金额:
$ 53.1万 - 项目类别:
Structure of HIV-1 envelope spike in the context of membrane
膜背景下 HIV-1 包膜刺突的结构
- 批准号:
10013609 - 财政年份:2020
- 资助金额:
$ 53.1万 - 项目类别:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
HIV-1 包膜尖峰识别辅助受体的结构基础
- 批准号:
9906847 - 财政年份:2018
- 资助金额:
$ 53.1万 - 项目类别:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
HIV-1 包膜尖峰识别辅助受体的结构基础
- 批准号:
10390469 - 财政年份:2018
- 资助金额:
$ 53.1万 - 项目类别:
Novel therapeutics targeting the membrane proximal external region of HIV-1 Env
针对 HIV-1 包膜近膜外部区域的新型疗法
- 批准号:
9513722 - 财政年份:2017
- 资助金额:
$ 53.1万 - 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:
10653205 - 财政年份:2016
- 资助金额:
$ 53.1万 - 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
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10449192 - 财政年份:2016
- 资助金额:
$ 53.1万 - 项目类别:
Small-Molecule Fusion Inhibitors Targeting a Fusion Intermediate State of HIV-1 g
针对 HIV-1 g 融合中间态的小分子融合抑制剂
- 批准号:
8901482 - 财政年份:2014
- 资助金额:
$ 53.1万 - 项目类别:
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