GPCR Network

GPCR网络

基本信息

批准号：
8289728
负责人：
RAYMOND C STEVENS
金额：
$ 34.11万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
https://reporter.nih.gov/project-details/8289728
关键词：
Address Adenosine A2A Receptor Adrenergic Agents Agonist Architecture Area Binding Sites Bioinformatics Biology Biomedical Research Cell Surface Receptors Collaborations Communities Community Outreach Complex Computer Simulation Core Facility Coupled Data Decision Making Deuterium Docking Educational workshop Enzymes Equilibrium Family Feedback G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Genes Genetic Variation Goals Guidelines Homologous Gene Human Human Genome Hydrogen Instruction Ion Channel Learning Ligand Binding Ligands Lipids Mass Spectrum Analysis Meleagris gallopavo Membrane Proteins Modeling Molecular Molecular Models NMR Spectroscopy Peptide Receptor Pharmaceutical Preparations Phylogenetic Analysis Physiological Process Production Property Protein Family Protein Structure Initiative Proteins Protocols documentation Publications Research Personnel Resolution Sampling Scientist Screening procedure Signal Transduction Site Solutions Structure System Technology Therapeutic Time Training Trees United States National Institutes of Health Visit adrenergic base cost experience extracellular human disease improved meetings member molecular modeling molecular recognition novel outreach preference protein expression protein purification protein structure receptor receptor binding response small molecule small molecule libraries structural biology success technology development tool

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 β2 adrenergic, turkey β1 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 homologs 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 蛋白偶联受体可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。他们共享七个共同的架构跨膜螺旋由广泛的细胞内和细胞外环和末端连接域。最近首次证明了该蛋白质家族结构测定的可行性对人 β2 肾上腺素、火鸡 β1 肾上腺素和人腺苷 A2A 的高分辨率研究受体。膜蛋白结构测定中心 (CMPD) 的成立是为了使用蛋白质家族特定平台，用于确定 15-20 个代表性 GPCR 的高分辨率结构分布在整个系统发育树上。受体结构需要具有生物学相关性粒度，用于小分子配体受体、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。每个受体结构将是用一组不同的药理学配体确定受体结合位点。解决方案将使用与不同配体结合的纯化受体进行研究，以了解受体使用氢-氘交换和核磁共振波谱进行动力学分析。与美国国立卫生研究院合作筛选中心，将使用小分子探针库来分析每个受体并发现使用高通量热稳定性筛选的变构结合位点。通过生物学信息选择代表性受体，我们将通过计算最大化 CMPD 的影响由外部合作者对密切同源物进行建模和功能研究，从而建立 PSI GPCR 网络。生成的数据将在与规定一致的时间范围内提供给社区蛋白质结构倡议的指导方针。技术获取将通过现场培训来实现，研讨会、会议和出版物。将提供对 CMPD 核心设施的处理访问权限通过为 PSI:Biology Network 提名目标提供 30% 的管道容量承诺。基于根据 CMPD 研究人员的经验，优先考虑人类或真核膜蛋白最大限度地利用 CMPD 功能。