GPCR Network

GPCR网络

基本信息

批准号：
8448475
负责人：
RAYMOND C STEVENS
金额：
$ 7.5万
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/8448475
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 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 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蛋白偶联受体感觉到了令人惊讶的细胞外分子信号，并触发复杂的细胞内和生理反应。它们共享了七个跨膜螺旋的共同结构，该螺旋螺旋通过各种范围的细胞内环和终端域连接。最近，通过对人β2肾上腺素能，土耳其β1肾上腺素能和人腺苷A2A受体进行的首次高分辨率研究证明了该蛋白质家族的结构确定性。已经创建了膜蛋白结构确定中心（CMPD），以使用蛋白质家族特异性平台来确定分布在整个系统发育树上的15-20代表性GPCR的高分辨率结构。在生物学相关的粒度上需要受体结构，对于小分子配体受体，肽和蛋白质受体，脂质受体，B-F受体，B-F受体以及活性和非活性功能状态中的受体。每个受体结构将用一组不同的药理配体确定，以定义受体结合位点。溶液研究将使用与不同配体结合的纯化受体进行，以使用氢核交换和NMR光谱学了解受体动力学。与NIH筛选中心合作，将使用一个小分子探针库来分析每个受体，并使用高吞吐量热稳定性屏幕来发现变构结合位点。通过对代表性受体的生物学知识选择，我们将通过外部合作者对近距离同源物和功能研究的计算建模，从而最大程度地发挥CMPD的影响，从而建立PSI GPCR网络。生成的数据将以符合蛋白质结构计划的指南的时间范围提供给社区。技术访问将通过现场培训，研讨会，会议和出版物来实现。处理CMPD核心设施的处理访问将通过PSI的30％管道能力承诺提供：生物网络提名目标。根据CMPD研究人员的经验，偏爱将偏爱人或真核膜蛋白，以最大程度地利用CMPD功能。