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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 GPCRs是一种在几乎所有人体组织中表达的膜蛋白，在不同的刺激(包括光、激素、损伤和炎症)下传递各种不同的信号。这些信号通过与GTP结合蛋白的相互作用调节一系列不同的细胞反应。许多急慢性疾病状态与GPCR功能或故障有关，40%-60%的商业可用药物与GPCR相互作用，使它们成为全球近30%药物发现努力的目标。1995年，这些药物的市场总额为840亿美元。到目前为止，已分离出300多个GPCR，并知道约150个GPCR的功能。据估计，人类基因组中存在约2000个GPCR。由于与生产这些完整的膜蛋白相关的困难，人们对GPCR的功能、结构、稳定性和组装的了解受到了阻碍。这个Cobre小型项目的目标是：1)建立制备具有功能活性的同位素富集型人A2a和人NK1受体的条件，并适用于核磁共振波谱的结构分析；2)获得上述受体的初步多维溶液或固态核磁共振谱，用于后续的结构分析。这些努力的长期目标是获得这些受体的原子级结构信息。该项目将加速膜蛋白GPCR族的结构研究，并使人们能够更好地理解这类令人着迷的蛋白质的配体识别。