STRUCTURE OF A GLUTAMATE RECEPTOR BINDING DOMAIN

谷氨酸受体结合域的结构

基本信息

批准号：
8171511
负责人：
ROBERT E OSWALD
金额：
$ 3.38万
依托单位：
CORNELL UNIVERSITY
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：
2010-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8171511
关键词：
Agonist Amyotrophic Lateral Sclerosis Binding Binding Sites Brain Cations Cell membrane Computer Retrieval of Information on Scientific Projects Database Disease Drug Delivery Systems Electron Spin Resonance Spectroscopy Epilepsy Extracellular Domain Funding GluR2 subunit AMPA receptor Glutamate Receptor Glutamates Grant Institution Ion Channel Ions Ischemic Brain Injury Length Ligand Binding Ligand Binding Domain Lobe Measurement Measures Motion NMR Spectroscopy Neurons Neurotransmitter Receptor Proteins Research Research Personnel Resources Source Structure United States National Institutes of Health Work X-Ray Crystallography extracellular flexibility protein function receptor binding

Agonist Amyotrophic Lateral Sclerosis Binding Binding Sites Brain Cations Cell membrane Computer Retrieval of Information on Scientific Projects Database Disease Drug Delivery Systems Electron Spin Resonance Spectroscopy Epilepsy Extracellular Domain Funding GluR2 subunit AMPA receptor Glutamate Receptor Glutamates Grant Institution Ion Channel Ions Ischemic Brain Injury Length Ligand Binding Ligand Binding Domain Lobe Measurement Measures Motion NMR Spectroscopy Neurons Neurotransmitter Receptor Proteins Research Research Personnel Resources Source Structure United States National Institutes of Health Work X-Ray Crystallography extracellular flexibility protein function receptor binding

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项目摘要

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. 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.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。谷氨酸受体是脊椎动物大脑中的主要兴奋性神经递质受体，参与了多种正常和病理神经元功能。这些蛋白质通过在细胞外结构域中结合谷氨酸并打开固有离子通道，从而使阳离子流入和流出神经元。针对谷氨酸受体的药物可能具有治疗诸如癫痫，肌萎缩性侧面硬化症和缺血性脑损伤等多种疾病的潜力。我们使用X射线晶体学以及NMR和ESR光谱研究了两个重要的谷氨酸受体（GLUR2和GLUR3），以了解结构和动力学，并将结果与使用单个通道记录测量的蛋白质的功能进行比较（在细胞膜中测量离子电导率的测量）。结构工作是在蛋白质的细胞外配体结合结构域（GlUR2 S1S2和GlUR3 S1S2）上完成的，该结构是从全长蛋白中得出的可溶构建体。蛋白质在两个裂片之间的界面处具有谷氨酸和衍生物的结合位点的双重结构。对于GlUR2，以前的工作表明，配体结合后裂片接近的程度可能与蛋白质的功能有关。我们与NMR光谱法和最近的晶体结构的最初工作表明，结构和功能之间的关系可能更复杂，涉及蛋白质柔韧性。在揭示可能的运动范围的条件下获得其他结构对于理解激动剂结合的功能后果至关重要。