Structure of HIV-1 envelope spike in the context of membrane
Structure of HIV-1 envelope spike in the context of membrane
批准号:
10538590
负责人:
Bing Chen
金额:
$53.1万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-01-16 至 2024-12-31
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
中文摘要
项目摘要
由HIV-1包膜糖蛋白[Env;三聚体(gp 160)3裂解为(gp 120/gp 41)3]介导的膜融合,
是病毒进入宿主细胞并建立感染的第一个关键步骤。成熟的Env峰含有
非共价结合的受体结合亚基GP 120和融合亚基GP 41各三个拷贝。一
广泛的生物化学和结构研究已经揭示了病毒膜融合的一般情况。
gp 120与主要受体CD 4和辅助受体的顺序结合导致大的、不可逆的结构改变。
gp 41中的重排,其驱动膜融合过程。尽管我们在这方面取得了巨大的进步,
在过去的二十年里,人们对HIV-1 Env结构的了解,主要是基于对其可溶性
尽管我们已经发现了一些片段,但我们仍然缺乏膜环境中全长Env的原子图像。一系列
最近的研究,我们已经确定了跨膜结构域,膜近端外部
区域,以及通过NMR模拟脂质双层的双胞中的HIV-1 Env的胞质尾的一部分。
出乎意料的是,我们发现这些区域在脂质双层的存在下都形成了有序的三聚体簇
并且它们中的任何一种的破坏都会降低膜融合效率并改变细胞的抗原结构。
整个环境,这表明他们发挥关键的结构和功能的作用。这些新发现提供了
确定脂质中重组的全长HIV-1 Env结构的强有力的科学前提
通过冷冻电子显微镜(cryoEM)观察纳米盘。我们假设跨膜和膜-
HIV-1 Env的近端区域全部采用对稳定性至关重要的确定的寡聚体结构,
膜全长蛋白的功能和抗原性。我们将利用最近的进展
在cryoEM和纳米盘技术中,并计划确定全长Env蛋白的结构,
在脂质双层中重构,单独或与基质蛋白复合。我们的目标是视觉化的小说
完整Env蛋白在膜环境中的结构特征,以充分了解其
结构-功能和促进用于疫苗开发的基于Env的免疫原设计。我们会把
以下具体目标:1)我们将在以下背景下确定全长HIV-1 Env的结构
2)我们将确定膜中完整Env抗原差异的结构基础
在具有不同抗体敏感性的HIV-1分离株中,3)我们将确定全长的结构,
HIV-1 Env与基质蛋白复合。
英文摘要
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.
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专著(0)
科研奖励(0)
会议论文
Exploring the membrane-related components of HIV-1 Env for immunogen design
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批准号:10762577
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项目类别:
-
资助金额:$84.19万
-
财政年份:2023
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负责人:Bing Chen
-
依托单位:
Structure of HIV-1 envelope spike in the context of membrane
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批准号:10322988
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项目类别:
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资助金额:$71.03万
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财政年份:2020
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负责人:Bing Chen
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依托单位:
Structure of the full-length spike protein of SARS-CoV-2 in the context of membrane
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批准号:10117733
-
项目类别:
-
资助金额:$53.1万
-
财政年份:2020
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负责人:Bing Chen
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依托单位:
Structure of HIV-1 envelope spike in the context of membrane
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批准号:10013609
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项目类别:
-
资助金额:$53.1万
-
财政年份:2020
-
负责人:Bing Chen
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依托单位:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
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批准号:9906847
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项目类别:
-
资助金额:$52.6万
-
财政年份:2018
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负责人:Bing Chen
-
依托单位:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
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批准号:10390469
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项目类别:
-
资助金额:$52.18万
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财政年份:2018
-
负责人:Bing Chen
-
依托单位:
Novel therapeutics targeting the membrane proximal external region of HIV-1 Env
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批准号:9513722
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项目类别:
-
资助金额:$67.38万
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财政年份:2017
-
负责人:Bing Chen
-
依托单位:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
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批准号:10653205
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项目类别:
-
资助金额:$81.62万
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财政年份:2016
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负责人:Bing Chen
-
依托单位:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
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批准号:10449192
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项目类别:
-
资助金额:$81.61万
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财政年份:2016
-
负责人:Bing Chen
-
依托单位:
Small-Molecule Fusion Inhibitors Targeting a Fusion Intermediate State of HIV-1 g
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批准号:8901482
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项目类别:
-
资助金额:$43.96万
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财政年份:2014
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负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:8603481
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项目类别:
-
资助金额:$41.26万
-
财政年份:2013
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:8663835
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项目类别:
-
资助金额:$44.15万
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财政年份:2013
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:9053443
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项目类别:
-
资助金额:$44.25万
-
财政年份:2013
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
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批准号:8836951
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项目类别:
-
资助金额:$44.25万
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财政年份:2013
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负责人:Bing Chen
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依托单位:
HIV-1 GP41 ARE RECOGNIZED BY NEUTRALIZING AND NON-NEUTRALIZING ANTIBODIES
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批准号:8361720
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项目类别:
-
资助金额:$0.26万
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财政年份:2011
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负责人:Bing Chen
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依托单位:
HIV-1 PRIMARY RECEPTOR CD4 IN COMPLEX WITH A POTENT ANTIVIRAL ANTIBODY
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批准号:8361719
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项目类别:
-
资助金额:$0.25万
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财政年份:2011
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负责人:Bing Chen
-
依托单位:
Biochemical and structural studies of distinct conformational states of gp41
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批准号:8055554
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项目类别:
-
资助金额:$35.18万
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财政年份:2009
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负责人:Bing Chen
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依托单位:
Biochemical and structural studies of distinct conformational states of gp41
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批准号:8243563
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项目类别:
-
资助金额:$35.39万
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财政年份:2009
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负责人:Bing Chen
-
依托单位:
Biochemical and structural studies of distinct conformational states of gp41
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批准号:7790795
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项目类别:
-
资助金额:$35.23万
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财政年份:2009
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负责人:Bing Chen
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依托单位:
Biochemical and structural studies of distinct conformational states of gp41
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批准号:8440765
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项目类别:
-
资助金额:$34.15万
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财政年份:2009
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负责人:Bing Chen
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依托单位:
海外基金