GPCR Network
GPCR网络
基本信息
- 批准号:8501563
- 负责人:
- 金额:$ 334.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-30 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenosine A2A ReceptorAdrenergic AgentsAgonistArchitectureAreaBinding SitesBioinformaticsBiologyBiomedical ResearchCell Surface ReceptorsCollaborationsCommunitiesCommunity OutreachComplexComputer SimulationCore FacilityCoupledDataDecision MakingDeuteriumDockingEducational workshopEnzymesEquilibriumFamilyFeedbackG Protein-Coupled Receptor GenesG-Protein-Coupled ReceptorsGenesGenetic VariationGoalsGuidelinesHomologous GeneHumanHuman GenomeHydrogenIon ChannelLearningLigand BindingLigandsLipidsMass Spectrum AnalysisMeleagris gallopavoMembrane ProteinsModelingMolecularMolecular ModelsNMR SpectroscopyPeptide ReceptorPharmaceutical PreparationsPhylogenetic AnalysisPhysiologicalProcessProductionPropertyProtein FamilyProtein Structure InitiativeProteinsProtocols documentationPublicationsResearch PersonnelResolutionSamplingScientistSignal TransductionSiteSolutionsStructureSystemTechnologyTherapeuticTimeTrainingTreesUnited States National Institutes of HealthVisitadrenergicbasecostexperienceextracellularhuman diseaseimprovedmeetingsmembermolecular modelingmolecular recognitionnoveloutreachpreferenceprotein expressionprotein purificationprotein structurereceptorreceptor bindingresponsescreeningsmall moleculesmall molecule librariesstructural biologysuccesstechnology developmenttool
项目摘要
G protein-coupled receptors sense an astonishing variety of extracellular molecular signals and trigger complex intracellular and physiological responses. They share a common architecture of seven transmembrane helices connected by a broad range of intra- and extra-cellular loops and terminal domains. Structure determination feasibility of this protein family was demonstrated recently with the first high resolution studies on the human Beta2 adrenergic, turkey Beta1 adrenergic, and human adenosine A2A receptors. The Center for Membrane Protein Structure Determination (CMPD) has been created to use a protein family specific platform to determine the high resolution structures of 15-20 representative GPCRs distributed across the phylogenetic tree. Receptor structures are needed at a biologically relevant granularity, for small molecule ligand receptors, peptide and protein receptors, lipid receptors, class B-F receptors, and of receptors in the active and inactive functional states. Each receptor structure will be determined with a set of different pharmacological ligands to define the receptor binding site(s). Solution studies will be conducted with purified receptors bound to different ligands to understand receptor dynamics using hydrogen-deuterium exchange and NMR spectroscopy. In collaboration with the NIH screening center, a library of small molecule probes will be used to analyze each receptor and discover allosteric binding sites using a high throughput thermal stability screen. Through a biologically informed selection of representative receptors, we will maximize the CMPD's impact through computational modeling of close homolog's and functional studies by external collaborators thereby establishing The PSI GPCR Network. The generated data will be provided to the community in a time frame consistent with the guidelines of the Protein Structure Initiative. Technology access will be achieved through on-site training, workshops, meetings, and publications. Processing access to the CMPD core facility will be provided through a 30% pipeline capacity commitment for the PSI: Biology Network nominated targets. Based on the experience of the CMPD investigators, preference will be for human or eukaryotic membrane proteins to maximally leverage the CMPD capabilities.
G蛋白偶联受体感知多种细胞外分子信号,并触发复杂的细胞内和生理反应。它们共享由广泛的细胞内和细胞外环和末端结构域连接的七个跨膜螺旋的共同结构。该蛋白质家族的结构测定可行性最近通过对人β 2肾上腺素能受体、火鸡β 1肾上腺素能受体和人腺苷A2 A受体的首次高分辨率研究得到证实。膜蛋白结构测定中心(CMPD)已创建,以使用蛋白质家族特异性平台来确定分布在系统发育树中的15-20个代表性GPCR的高分辨率结构。对于小分子配体受体、肽和蛋白质受体、脂质受体、B-F类受体以及处于活性和非活性功能状态的受体,需要生物学相关粒度的受体结构。将用一组不同的药理学配体确定每种受体结构,以确定受体结合位点。将使用与不同配体结合的纯化受体进行溶液研究,以使用氢氘交换和NMR光谱法了解受体动力学。与NIH筛选中心合作,将使用小分子探针库分析每个受体,并使用高通量热稳定性筛选发现变构结合位点。通过对代表性受体的生物学选择,我们将 最大限度地提高CMPD的影响,通过计算模拟密切同源的和功能的研究,由外部合作者,从而建立PSI GPCR网络。生成的数据将在符合蛋白质结构倡议指导方针的时间框架内提供给社区。将通过现场培训、讲习班、会议和出版物获得技术。CMPD核心设施的处理权限将通过PSI:生物网络提名目标的30%管道容量承诺提供。根据CMPD研究者的经验,优先选择人或真核细胞膜蛋白,以最大限度地利用CMPD的能力。
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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RAYMOND C STEVENS其他文献
RAYMOND C STEVENS的其他文献
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{{ truncateString('RAYMOND C STEVENS', 18)}}的其他基金
Platform for Structure-Function Studies of Adhesion GPCRs implicated in Cancer
与癌症相关的粘附 GPCR 的结构功能研究平台
- 批准号:
8926375 - 财政年份:2015
- 资助金额:
$ 334.48万 - 项目类别:
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