Subunit Assembly and Substrate Interactions in HIV-1 RT
HIV-1 RT 中的亚基组装和底物相互作用
基本信息
- 批准号:7930208
- 负责人:
- 金额:$ 43.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2011-08-28
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeActive SitesAdverse effectsAntiviral TherapyArtsBindingBiochemicalBiological AssayC-terminalChromosomesClinicalComplexCysteineDBL OncoproteinDNADNA BindingDNA-Directed DNA PolymeraseDevelopmentDimerizationDissociationDrug effect disorderDrug resistanceEnergy TransferEngineeringEnzymesEquilibriumFluorescenceFluorescence AnisotropyFluorescent ProbesFutureGelGenerationsGenomicsGoalsHIVHIV InfectionsHIV IntegraseHIV ProteaseHIV therapyHIV-1IndividualInvestigationKineticsKnowledgeLaboratoriesLifeLigandsLinkMeasurementMeasuresMethodsMolecularMolecular ConformationMolecular TargetMonitorMutationNevirapineNucleotidesPharmaceutical PreparationsPolymeraseProcessProtein ConformationProteinsRNARNA primersRNA-Directed DNA PolymeraseReactionResearch PersonnelReverse Transcriptase InhibitorsRibonuclease HSiteSolutionsSpecificityStructureSubstrate InteractionTechniquesTestingTherapeuticTimeUnited Statesbaseconformational conversiondesigndimerefavirenzenzyme activityflexibilityhigh throughput screeningimprovedinhibitor/antagonistinsightmonomermutantnon-nucleoside reverse transcriptase inhibitorspolymerizationprogramsprotein protein interactionresearch studyresistance mechanismsedimentation equilibriumsingle moleculestop flow techniquestopped-flow fluorescence
项目摘要
The goal of this proposal is to investigate protein-ligand and protein-protein interactions in HIV-1 reverse
transcriptase (RT). Being a key player in HIV infection, RT is the molecular target of the majority of AIDS
drugs. Ligands studied will include five nonnucleoside reverse transcriptase inhbitiors (NNRTI) as well as
normal substrates. RTs studied will include up to five drug resistance mutants in addition to wild type. The
enzyme copies the single-stranded genomic RNA into a double-stranded DMAprovirus, which is
subsequently integrated into the host chromosome by HIV integrase. RT has RNA- and DMA-dependent
DMA polymerase and RNase H activities. The biologically active enzyme is a heterodimer of p66 and p51
subunits. The p51 subunit is derived from p66 subunit by HIV protease. The proposal applies biochemical
and biophysical techniques, including powerful site-specific fluorescence techniques, to fundamental
investigations of proposed inhibition mechanisms and protein conformations that may reveal new targets for
antiviral therapy. This laboratory is presently one of few using solution biophysical techniques to study RT.
Specifically, we propose to:
1. Characterize inhibitor binding to RT.
2. Determine inhibitor effects on individual steps in DMA polymerization.
3. Investigate inhibitor effects on conformation and dynamics of RT subunits and assembly.
该提案的目标是研究HIV-1逆转录病毒中的蛋白质-配体和蛋白质-蛋白质相互作用
转录酶(RT)。RT是HIV感染的关键分子,是大多数AIDS的分子靶点
毒品研究的配体将包括五种非核苷逆转录酶抑制剂(NNRTI)以及
正常基质。除了野生型之外,研究的RT将包括多达5种耐药突变体。的
酶将单链基因组RNA复制成双链DMA原病毒,
随后通过HIV整合酶整合到宿主染色体中。RT具有RNA和DMA依赖性
DNA聚合酶和RNase H活性。生物活性酶是p66和p51的异源二聚体
亚单位。p51亚基由HIV蛋白酶从p66亚基衍生而来。该提案适用于生物化学
和生物物理技术,包括强大的位点特异性荧光技术,
研究提出的抑制机制和蛋白质构象,可能揭示新的目标,
抗病毒治疗该实验室是目前为数不多的使用溶液生物物理技术研究RT的实验室之一。
具体而言,我们建议:
1.表征抑制剂与RT的结合。
2.测定阻聚剂对DMA聚合中各个步骤的影响。
3.研究抑制剂对RT亚基构象和动力学的影响。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Separation of protein oligomers by blue native gel electrophoresis.
- DOI:10.1016/j.ab.2009.02.019
- 发表时间:2009-05-01
- 期刊:
- 影响因子:2.9
- 作者:Braz VA;Howard KJ
- 通讯作者:Howard KJ
Efavirenz binding to HIV-1 reverse transcriptase monomers and dimers.
- DOI:10.1021/bi901579y
- 发表时间:2010-01-26
- 期刊:
- 影响因子:2.9
- 作者:Braz, Valerie A.;Holladay, Leslie A.;Barkley, Mary D.
- 通讯作者:Barkley, Mary D.
Allosteric suppression of HIV-1 reverse transcriptase structural dynamics upon inhibitor binding.
- DOI:10.1016/j.bpj.2010.11.004
- 发表时间:2011-01
- 期刊:
- 影响因子:3.4
- 作者:James M. Seckler;M. Barkley;P. Wintrode
- 通讯作者:James M. Seckler;M. Barkley;P. Wintrode
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MARY D BARKLEY其他文献
MARY D BARKLEY的其他文献
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{{ truncateString('MARY D BARKLEY', 18)}}的其他基金
Subunit Assembly and Substrate Interactions in HIV-1 RT
HIV-1 RT 中的亚基组装和底物相互作用
- 批准号:
7367969 - 财政年份:2006
- 资助金额:
$ 43.99万 - 项目类别:
Subunit Assembly and Substrate Interactions in HIV-1 RT
HIV-1 RT 中的亚基组装和底物相互作用
- 批准号:
7105246 - 财政年份:2006
- 资助金额:
$ 43.99万 - 项目类别:
Subunit Assembly and Substrate Interactions in HIV-1 RT
HIV-1 RT 中的亚基组装和底物相互作用
- 批准号:
7578248 - 财政年份:2006
- 资助金额:
$ 43.99万 - 项目类别:
Subunit Assembly and Substrate Interactions in HIV-1 RT
HIV-1 RT 中的亚基组装和底物相互作用
- 批准号:
7197365 - 财政年份:2006
- 资助金额:
$ 43.99万 - 项目类别:
BIOCHEMICAL EVALUATION OF RT-TEMPLATE-PRIMER/COMPLEXES
RT 模板引物/复合物的生化评价
- 批准号:
2652106 - 财政年份:1994
- 资助金额:
$ 43.99万 - 项目类别:
BIOCHEMICAL EVALUATION OF RT-TEMPLATE-PRIMER/COMPLEXES
RT 模板引物/复合物的生化评价
- 批准号:
6386122 - 财政年份:1994
- 资助金额:
$ 43.99万 - 项目类别:
BIOCHEMICAL EVALUATION OF RT-TEMPLATE-PRIMER/COMPLEXES
RT 模板引物/复合物的生化评价
- 批准号:
6180611 - 财政年份:1994
- 资助金额:
$ 43.99万 - 项目类别:
BIOCHEMICAL EVALUATION OF RT-TEMPLATE-PRIMER/COMPLEXES
RT 模板引物/复合物的生化评价
- 批准号:
6019052 - 财政年份:1994
- 资助金额:
$ 43.99万 - 项目类别:
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