Biochemical and structural studies of distinct conformational states of gp41
Biochemical and structural studies of distinct conformational states of gp41
批准号:
8440765
负责人:
Bing Chen
金额:
$34.15万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-04-01 至 2015-03-31
关键词:
AIDS VaccinesAcquired Immunodeficiency SyndromeAffinity ChromatographyAntibodiesAntiviral AgentsBindingBiochemicalBiological AssayCell membraneCellsCharacteristicsComplementComplexCrystallizationDataDetergentsDevelopmentElectron MicroscopyElectronsEpidemicEpitopesEscherichia coliGenerationsGlycoproteinsGoalsHIVHIV Envelope Protein gp120HIV-1ImageImmune responseIn VitroInsectaKnowledgeLifeLightMediatingMembraneMembrane FusionModelingMolecularMolecular ConformationMutagenesisMutateNMR SpectroscopyPathway interactionsPeptidesPreparationProductionPropertyProteinsRecombinantsResidual stateResolutionSIVSIV envelope protein gp41SeriesSiteStructureSurfaceT-20TestingTherapeuticTransmembrane DomainUpdateVaccinesViralVirionVirus Receptorsbaseconformational conversiondesignenv Gene Productsglycosylationin vivoinhibitor/antagonistinsightneutralizing antibodyprotein S precursorprotein structurereceptorresearch studyretinal rodsscreeningsimian immunodeficiency virus gp120therapeutic vaccineurinary gonadotropin fragmentvaccine development
中文摘要
HIV/SIV包膜糖蛋白组装成(gp120/gp41)3三聚体复合体,介导病毒
附着和膜融合。生化和结构研究提供了一个大致的图景
与病毒受体和辅受体的结合触发了一系列促进融合的构象变化。
在原子水平上对HIV/SIV环境构象的理解主要来自三组晶体
结构:未连接的SIV gp120核心片段、HIV受体诱导构象的结构
Gp120核心,以及HIV和SIV融合后形式的gp41。原住民的构象
(gp120/gp41)3病毒粒子表面,特别是其gp41组分的表面仍然未知,除了
一些来自电子显微镜的低分辨率图像。我们也缺乏一张重要的
Gp41从融合前到融合后构象的中间产物--所谓的“前发夹”
中间体“,这是T-20/恩福韦肽(第一个被批准的融合抑制抗病毒药物)和
某些广谱中和抗体,正如我们在初步数据中所描述的那样。填补我们在以下方面的空白
对包膜蛋白结构的了解将指导疫苗和疗法的发展。此外,
生产稳定、均一的具有特定构象的重组gp41制剂将有助于我们
了解中和的结构相关性,即使在没有高分辨率结构的情况下也是如此。在这
提案中,我们将探讨gp41的各种构象状态对我们的
通过生化和结构方法了解融合机制和抗体中和。我们
建议在此研究gp41的前融合构象、融合中间构象和融合后构象。
信息是我们的终极目标。我们将以初步结果为基础,表明我们可以表达和
描述每一种的适当形式。特别是,我们将追求以下具体目标:1.开展
Gp41“发夹前中间体”的生化和结构研究
预融合构象及其结构测定;3.膜相互作用构象的研究
融合后状态的gp41片段。
英文摘要
The envelope glycoproteins of HIV/SIV, assembled as a (gp120/gp41)3 trimeric complex, mediate viral
attachment and membrane fusion. Biochemical and structural studies have provided a general picture of how
binding to viral receptor and co-receptor triggers a cascade of fusion-promoting conformational changes.
Understanding of HIV/SIV Env conformations at the atomic level has come mainly from three sets of crystal
structures: that of an unliganded SIV gp120 core fragment, those of receptor-induced conformations of the HIV
gp120 core, and those of the postfusion form of HIV and SIV gp41. The conformation of the native
(gp120/gp41)3 on the surface of the virion, especially that of its gp41 component, remains unknown, except for
some low-resolution images from electron microscopy. We also lack a proper picture of an important
intermediate in the pathway from the prefusion to postfusion conformation of gp41 - the so-called "prehairpin
intermediate" that is the target of T-20/Entfuvirtide (the first approved fusion-inhibiting antiviral drug) and of
certain broadly neutralizing antibodies, as we describe in the Preliminary Data. Filling these gaps in our
knowledge of envelope protein structures will guide development of vaccines and therapeutics. Moreover,
production of stable, homogeneous preparations of recombinant gp41 in defined conformations will help us
understand structural correlates for neutralization, even in the absence of high-resolution structures. In this
proposal, we will explore the hypothesis that the various conformational states of gp41 hold key to our
understanding of fusion mechanism and antibody neutralization by biochemical and structural approaches. We
propose here to study gp41 in its prefusion, fusion-intermediate, and postfusion conformations, with structural
information as our ultimate goal. We will build upon preliminary results that show we can express and
characterize suitable forms of each. In particular, we will pursue the following specific aims: 1. To carry out
biochemical and structural studies of the "prehairpin intermediate" of gp41; 2. To characterize gp41 in the
prefusion conformation and determine its structure; 3. To study the conformation of the membrane-interacting
segments of gp41 in the postfusion state.
期刊论文(0)
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:
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资助金额:$84.19万
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财政年份:2023
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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: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 HIV-1 envelope spike in the context of membrane
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批准号:10538590
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项目类别:
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资助金额:$53.1万
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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
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项目类别:
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资助金额:$53.1万
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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 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:
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资助金额:$53.1万
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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:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
-
批准号:9906847
-
项目类别:
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资助金额:$52.6万
-
财政年份:2018
-
负责人:Bing Chen
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依托单位:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
-
批准号:10390469
-
项目类别:
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资助金额:$52.18万
-
财政年份:2018
-
负责人:Bing Chen
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依托单位:
Novel therapeutics targeting the membrane proximal external region of HIV-1 Env
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批准号:9513722
-
项目类别:
-
资助金额:$67.38万
-
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
-
批准号:10653205
-
项目类别:
-
资助金额:$81.62万
-
财政年份:2016
-
负责人:Bing Chen
-
依托单位:
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
-
批准号:10449192
-
项目类别:
-
资助金额:$81.61万
-
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
-
项目类别:
-
资助金额:$43.96万
-
财政年份:2014
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
-
批准号:8603481
-
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
-
批准号:8663835
-
项目类别:
-
资助金额:$44.15万
-
财政年份:2013
-
负责人:Bing Chen
-
依托单位:
Crystallographic studies of intact and fully glycosylated HIV-1 gp120
-
批准号:9053443
-
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
-
批准号:8836951
-
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:
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
-
财政年份:2011
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负责人:Bing Chen
-
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
-
财政年份:2011
-
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
-
财政年份:2009
-
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:8243563
-
项目类别:
-
资助金额:$35.39万
-
财政年份:2009
-
负责人:Bing Chen
-
依托单位:
Biochemical and structural studies of distinct conformational states of gp41
-
批准号:7790795
-
项目类别:
-
资助金额:$35.23万
-
财政年份:2009
-
负责人:Bing Chen
-
依托单位:
海外基金