Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
Structure-function studies of the membrane-interacting domains of HIV-1 Env spike
批准号:
10653205
负责人:
Bing Chen
金额:
$81.62万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
未结题
起止时间:
2016-05-20 至 2026-06-30
关键词:
2019-nCoVAcquired Immunodeficiency SyndromeAdoptedAlanineAnimal ModelArchitectureBiogenesisBiological AssayCOVID-19 pandemicCell fusionCellsChimeric ProteinsComputer ModelsCoupledCryoelectron MicroscopyCytoplasmic TailData AnalysesDetergentsDiseaseElementsEnvironmentFundingGoalsHIVHIV-1InfectionInterventionLengthLipid BilayersLipidsMacaca mulattaMembraneMembrane FusionMembrane ProteinsMolecular ConformationMutagenesisPeptidesPhysiologicalPlayPreparationProcessPropertyProteinsProtocols documentationResearchResolutionRoleSARS-CoV-2 spike proteinSIVSamplingScanningStructureTailTechnologyTestingTransmembrane DomainVaccinesViralViral Fusion ProteinsVirusVirus AssemblyVirus DiseasesVisualizationenv Gene Productsfascinatefightinginsightnanodisc technologynanodisknovelprotein foldingprotein reconstitutionprotein structuretherapeutic developmenttherapeutic targettherapy developmentvaccine developmentvaccine trial
中文摘要
项目摘要
包膜病毒(如HIV-1)进入宿主细胞的第一个关键步骤是病毒膜融合。
病毒融合蛋白是一种迷人的蛋白质折叠机器,能够采用完全不同的蛋白质结构。
它们在融合过程中具有构象;它们也是重要的疫苗和治疗靶标。先前
研究已经揭示了许多病毒融合蛋白的可溶性片段的融合前和融合后构象
蛋白质,但较少知道其融合肽,跨膜和膜近端的结构
在脂质双层的背景下的区域。有强有力的证据表明膜的功能作用-
相互作用的区域融合,但机制的研究,他们如何发挥其功能仍然很少。我们
假设与HIV-1包膜相关其他融合蛋白的膜相互作用区域
蛋白(Env)采用确定的寡聚体结构,这些结构对稳定性、功能和
膜中全长蛋白的抗原性。在我们之前完成的研究中,
资金期间,我们已经确定了TM的结构,膜近端外部区域,
使用最新的NMR技术,在模拟脂质双层的双胞中检测HIV-1 Env的胞质尾区。我们发现
这些区域都形成有序的三聚体簇,并且在构象上偶联,
可以减少融合并改变整个Env的抗原结构。在本申请中,我们建议
我们的NMR/bicelle技术来研究SIV Env和最近出现的SARS的膜区域,
CoV-2 spike(S),并使用冷冻电子显微镜确定全长蛋白质的结构
在脂质纳米盘中重构。我们将定义这些关键结构元件在膜融合中的作用,
区域通过深度诱变和功能测定。我们将追求以下具体目标:1)我们将
研究SIV Env的膜相互作用组分; 2)我们将研究SIV Env的膜相互作用组分。
融合后安排中的成分; 3)我们将确定全长SIV Env的结构,
SARS-CoV-2S在膜环境中的作用; 4)我们将阐明SARS-CoV-2S的膜相互作用结构域的作用。
HIV/SIV Env和SARS-CoV-2S的稳定性、功能和抗原性。
英文摘要
Project Summary
The first critical step for enveloped viruses, such as HIV-1, to enter host cells is viral membrane fusion.
Viral fusion proteins are fascinating protein folding machineries capable of adopting completely different
conformations during the fusion process; they are also important vaccine and therapeutic targets. Previous
studies have revealed both pre- and post-fusion conformations of the soluble fragments of many viral fusion
proteins, but less is known for structures of their fusion peptide, transmembrane and membrane-proximal
regions in the context of lipid bilayers. There is strong evidence for functional roles of the membrane-
interacting regions in fusion, and yet mechanistic studies on how they exert their functions remain scarce. We
hypothesize that membrane-interacting regions of other fusion proteins related to HIV-1 envelope
protein (Env) adopt defined oligomeric structures that are critical for the stability, function and
antigenicity of the full-length proteins in membrane. In the studies that we completed during the previous
funding period, we have determined the structures of the TM, membrane proximal external region, and
cytoplasmic tail of HIV-1 Env in bicelles that mimic lipid bilayers using the latest NMR technology. We find that
these regions all form well-ordered trimeric clusters and are conformationally coupled, and that disrupting them
can reduce fusion and alter the antigenic structure of the entire Env. In this application, we propose to apply
our NMR/bicelle technology to investigate the membrane regions of SIV Env and the recently emerged SARS-
CoV-2 spike (S), and to use cryo-electron microscopy to determine structures of the full-length proteins
reconstituted in lipid nanodiscs. We will define roles in membrane fusion of critical structural elements of these
regions by deep mutagenesis and functional assays. We will purse the following specific aims: 1) we will
investigate the membrane-interacting components of SIV Env; 2) we will investigate the membrane-interacting
components in the postfusion arrangement; 3) we will determine structures of the full-length SIV Env and
SARS-CoV-2 S in the context of membrane; 4) we will elucidate roles of the membrane-interacting domains of
HIV/SIV Env and SARS-CoV-2 S in their stability, function and antigenicity.
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DOI:
10.1111/febs.13954
发表时间:
2017-04
期刊:
The FEBS journal
影响因子:
--
作者:
[Chen B, Chou JJ]
通讯作者:
Chou JJ
Conformational States of a Soluble, Uncleaved HIV-1 Envelope Trimer.
可溶、未切割的 HIV-1 包膜三聚体的构象状态。
DOI:
10.1128/jvi.00175-17
发表时间:
2017
期刊:
Journal of virology
影响因子:
5.4
作者:
[Liu,Yuhang, Pan,Junhua, Cai,Yongfei, Grigorieff,Nikolaus, Harrison,StephenC, Chen,Bing]
通讯作者:
Chen,Bing
DOI:
10.1126/science.aaf7066
发表时间:
2016-07-08
期刊:
Science (New York, N.Y.)
影响因子:
--
作者:
[Dev J, Park D, Fu Q, Chen J, Ha HJ, Ghantous F, Herrmann T, Chang W, Liu Z, Frey G, Seaman MS, Chen B, Chou JJ]
通讯作者:
Chou JJ
DOI:
10.1021/jacs.7b09352
发表时间:
2017-12-27
期刊:
Journal of the American Chemical Society
影响因子:
15
作者:
[Piai A, Dev J, Fu Q, Chou JJ]
通讯作者:
Chou JJ
Exploring the membrane-related components of HIV-1 Env for immunogen design
-
批准号:10762577
-
项目类别:
-
资助金额:$84.19万
-
财政年份:2023
-
负责人:Bing Chen
-
依托单位:
Structure of HIV-1 envelope spike in the context of membrane
-
批准号:10322988
-
项目类别:
-
资助金额:$71.03万
-
财政年份:2020
-
负责人:Bing Chen
-
依托单位:
Structure of HIV-1 envelope spike in the context of membrane
-
批准号:10538590
-
项目类别:
-
资助金额:$53.1万
-
财政年份:2020
-
负责人:Bing Chen
-
依托单位:
Structure of the full-length spike protein of SARS-CoV-2 in the context of membrane
-
批准号:10117733
-
项目类别:
-
资助金额:$53.1万
-
财政年份:2020
-
负责人:Bing Chen
-
依托单位:
Structure of HIV-1 envelope spike in the context of membrane
-
批准号:10013609
-
项目类别:
-
资助金额:$53.1万
-
财政年份:2020
-
负责人:Bing Chen
-
依托单位:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
-
批准号:9906847
-
项目类别:
-
资助金额:$52.6万
-
财政年份:2018
-
负责人:Bing Chen
-
依托单位:
Structural Basis of Coreceptor Recognition by HIV-1 Envelope Spike
-
批准号:10390469
-
项目类别:
-
资助金额:$52.18万
-
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
-
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: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
-
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
-
批准号:8361720
-
项目类别:
-
资助金额:$0.26万
-
财政年份:2011
-
负责人:Bing Chen
-
依托单位:
HIV-1 PRIMARY RECEPTOR CD4 IN COMPLEX WITH A POTENT ANTIVIRAL ANTIBODY
-
批准号:8361719
-
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
-
批准号:8055554
-
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
-
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:
Biochemical and structural studies of distinct conformational states of gp41
-
批准号:8440765
-
项目类别:
-
资助金额:$34.15万
-
财政年份:2009
-
负责人:Bing Chen
-
依托单位:
海外基金