STRUCTURE OF A GLUTAMATE RECEPTOR BINDING DOMAIN

谷氨酸受体结合域的结构

• 批准号: 8363530
• 负责人: ROBERT E OSWALD
• 金额: $ 4.01万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363530
• 关键词: Agonist; Amyotrophic Lateral Sclerosis; Binding; Binding Sites; Brain; Cations; Cell membrane; Disease; Drug Delivery Systems; Electron Spin Resonance Spectroscopy; Epilepsy; Extracellular Domain; Funding; GluR2 subunit AMPA receptor; Glutamate Receptor; Glutamates; Grant; Ion Channel; Ions; Ischemic Brain Injury; Length; Ligand Binding; Ligand Binding Domain; Lobe; Measurement; Measures; Motion; NMR Spectroscopy; National Center for Research Resources; Neurons; Neurotransmitter Receptor; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Source; Structure; United States National Institutes of Health; Work; X-Ray Crystallography; cost; extracellular; flexibility; protein function; receptor binding

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Glutamate receptors are the major excitatory neurotransmitter receptors in vertebrate brain and are involved in a variety of normal and pathological neuronal functions. These proteins function by binding glutamate in an extracellular domain and opening an intrinsic ion channel that allows cations to flow in and out of the neuron. Drugs targeted to glutamate receptors may have considerable potential for treating such diverse disorders as epilepsy, amyotrophic lateral sclerosis, and ischemic brain damage. We are studying two important glutamate receptors (GluR2 and GluR3), using X-ray crystallography and NMR and ESR spectroscopy to understand the structure and dynamics and to compare the results with the function of the protein measured using single channel recording (measurement of ion conductance across the cell membrane). The structural work is done on the extracellular ligand-binding domains of the proteins (GluR2 S1S2 and GluR3 S1S2), which are a soluble constructs derived from the full-length proteins. The proteins have a bilobed structure with the binding site for glutamate and derivatives at the interface between the two lobes. For GluR2, previous work has suggested that the degree to which the lobes close upon binding of ligand may relate to the function of the protein. Our initial work with NMR spectroscopy and our recent crystal structures, suggest that the relationship between structure and function may be more complicated, involving protein flexibility. Obtaining additional structures, under conditions that reveal the range of possible motions, is essential for understanding the functional consequences of agonist binding.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 谷氨酸受体是脊椎动物脑内主要的兴奋性神经递质受体，参与多种正常和病理的神经功能。这些蛋白质通过在细胞外区域结合谷氨酸，并打开允许阳离子流入和流出神经元的内在离子通道来发挥作用。针对谷氨酸受体的药物可能在治疗癫痫、肌萎缩侧索硬化症和缺血性脑损伤等多种疾病方面具有相当大的潜力。我们正在研究两个重要的谷氨酸受体(GluR2和GluR3)，使用X射线结晶学和核磁共振和ESR光谱来了解其结构和动力学，并将结果与使用单通道记录(跨细胞膜离子电导测量)测量的蛋白质功能进行比较。结构工作是在蛋白质(GluR2 S1S2和GluR3 S1S2)的胞外配体结合域上进行的，这些蛋白质是由全长蛋白质衍生的可溶结构物。这些蛋白质具有双叶结构，谷氨酸及其衍生物的结合位置在两个叶之间的界面上。对于GluR2，以前的工作表明，结合配体时叶关闭的程度可能与蛋白质的功能有关。我们对核磁共振波谱和最近的晶体结构的初步工作表明，结构和功能之间的关系可能更复杂，涉及蛋白质的灵活性。在揭示可能运动范围的条件下获得额外的结构，对于理解激动剂结合的功能后果是必不可少的。