GPCR Network

GPCR网络

基本信息

批准号：
8324098
负责人：
RAYMOND C STEVENS
金额：
$ 18.95万
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/8324098
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蛋白偶联受体感觉到了令人惊讶的细胞外分子信号和触发复杂的细胞内和生理反应。他们共享七个共同的建筑通过广泛的细胞内和末端连接的跨膜螺旋域。最近证明了该蛋白质家族的结构确定可行性对人β2肾上腺素，土耳其β1肾上腺素和人腺苷A2A的高分辨率研究受体。已经创建了膜蛋白结构确定中心（CMPD）蛋白质家族特定平台，以确定15-20代表性GPCR的高分辨率结构分布在系统发育树上。在生物学上相关的受体结构需要受体结构粒度，用于小分子配体受体，肽和蛋白质受体，脂质受体，B类受体和活性功能状态中的受体。每个受体结构将是用一组不同的药理配体确定以定义受体结合位点。解决方案研究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 - 居民交换和NMR光谱法的动力学。与NIH合作筛选中心，小分子探针的库将用于分析每个受体并发现变构结合位点使用高吞吐量热稳定性屏幕。通过生物学知情选择代表性受体，我们将通过计算最大化CMPD的影响外部合作者对近距离同源物和功能研究的建模，从而建立PSI GPCR网络。生成的数据将以与蛋白质结构计划的指南。技术访问将通过现场培训来实现讲习班，会议和出版物。将提供对CMPD核心设施的处理访问通过对PSI的30％管道能力承诺：生物网络提名目标。基于 CMPD研究人员的经验，偏爱将是人类或真核膜蛋白而不是最大程度地利用CMPD功能。