TOWARDS SOLID-STATE NMR STRUCTURES OF GPCRS

GPCRS 的固态核磁共振结构

• 批准号: 7959542
• 负责人: Tatyana Polenova
• 金额: $ 6.89万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959542
• 关键词: Acute; Centers of Research Excellence; Chronic Disease; Computer Retrieval of Information on Scientific Projects Database; Discrimination; Family; Funding; G Protein-Coupled Receptor Genes; GTP-Binding Proteins; Goals; Grant; Hormones; Human; Human Genome; Inflammation; Injury; Institution; Integral Membrane Protein; Ligands; Light; Link; Marketing; Membrane Proteins; NMR Spectroscopy; Pharmaceutical Preparations; Production; Proteins; Research; Research Personnel; Resources; Signal Transduction; Solutions; Source; Stimulus; Structure; United States National Institutes of Health; drug discovery; fascinate; human tissue; improved; receptor; response; solid state nuclear magnetic resonance

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. GPCRs are membrane proteins expressed in virtually all human tissues, and transmit a wide variety of signals in response to diverse stimuli (including light, hormones, injury, and inflammation). These signals regulate a diverse set of cellular responses via interaction with GTP-binding proteins. Many acute and chronic disease states are linked to GPCR function or malfunction, and 40-60% of commercially available drugs interact with a GPCR, making them targets for nearly 30% of drug discovery efforts worldwide. Together these drugs had an $84 billion market in 1995. Thus far over 300 GPCRs have been isolated, and the functions of about 150 are known. It is estimated that ~2000 GPCRs exist in the human genome. Efforts to understand GPCR function, structure, stability, and assembly are hampered by the difficulties associated with producing these integral membrane proteins. The goals of this COBRE mini-project are: 1) to establish the conditions for preparing isotopically enriched human A2a and human NK1 receptors in their functionally competent forms, and suitable for structural analysis by NMR spectroscopy, and 2) to acquire preliminary multidimensional solution or solid-state NMR spectra of the above receptors, for subsequent structural analysis. The long term goal of these efforts is to gain atomic-level structural information of these receptors. This project will accelerate the structural studies of the GPCR family of membrane proteins and enable an improved understanding of the ligand discrimination of this fascinating class of proteins.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 GPCR 是几乎在所有人体组织中表达的膜蛋白，可传递多种信号以响应不同的刺激（包括光、激素、损伤和炎症）。 这些信号通过与 GTP 结合蛋白相互作用来调节多种细胞反应。许多急性和慢性疾病状态与 GPCR 功能或故障有关，40-60% 的市售药物与 GPCR 相互作用，这使得它们成为全球近 30% 药物发现工作的目标。 1995 年，这些药物的市场总额达到 840 亿美元。迄今为止，已分离出 300 多个 GPCR，其中约 150 个的功能是已知的。据估计，人类基因组中存在约 2000 个 GPCR。生产这些整合膜蛋白的困难阻碍了了解 GPCR 功能、结构、稳定性和组装的努力。 该 COBRE 迷你项目的目标是：1) 建立以功能形式制备同位素富集的人类 A2a 和人类 NK1 受体的条件，并适合通过 NMR 光谱进行结构分析，以及 2) 获得初步的多维解决方案或上述受体的固态NMR谱，用于后续结构分析。 这些努力的长期目标是获得这些受体的原子级结构信息。 该项目将加速 GPCR 膜蛋白家族的结构研究，并加深对这一类令人着迷的蛋白质的配体辨别的理解。