Structural dynamics and function of the glutamate receptor ligand-binding domain

谷氨酸受体配体结合域的结构动力学和功能

• 批准号: 8137267
• 负责人: ALBERT Y LAU
• 金额: $ 26.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-03 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137267
• 关键词: AMPA Receptors; Accounting; Agonist; Amino Acids; Behavior; Binding; Binding Sites; Brain; Cations; Cell membrane; Chemicals; Complex; Coupling; DNA Sequence Rearrangement; Data; Distant; Docking; Drug Delivery Systems; Family; Free Energy; Functional disorder; Gated Ion Channel; Generations; Glutamate Receptor; Glutamates; Goals; Health; Investigation; Ion Channel; Joints; Kainic Acid Receptors; Knowledge; Ligand Binding; Ligand Binding Domain; Ligands; Measurement; Measures; Mediating; Mental disorders; Methodology; Microscopic; Modeling; Molecular; Molecular Conformation; N-Methyl-D-Aspartate Receptors; Nerve; Neurodegenerative Disorders; Neurons; Neurotransmitters; Population; Process; Proteins; Receptor Activation; Regulation; Research; Research Project Grants; Roentgen Rays; Role; Sensory Receptors; Signal Transduction; Site; Solutions; Spinal Cord; Structure; Surface Plasmon Resonance; Synapses; System; Testing; Therapeutic Agents; Therapeutic Intervention; Transmembrane Domain; Work; X-Ray Crystallography; base; computer studies; conformational conversion; crosslink; delta opioid receptor; desensitization; design; dimer; flexibility; monomer; nervous system disorder; novel; postsynaptic; receptor; receptor function; research study; response; simulation

DESCRIPTION (provided by applicant): Ligand-gated ion channels mediate information transfer at synapses. The binding of neurotransmitter molecules to the ligand-binding domains (LBDs) of these channels drive the opening of transmembrane pores, allowing cations to flow across the cell membrane to trigger the generation of a nerve impulse in the postsynaptic neuron. The site of agonist binding is usually distant from the transmembrane pore, so activation of the channel must be mediated by allosteric coupling of conformational changes at the binding site to corresponding changes at the channel's gate. The ionotropic glutamate receptor ion channels (iGluRs) mediate excitatory responses at the vast majority of synapses in the brain and spinal cord. A growing body of evidence indicates that iGluRs have key roles in a broad variety of neurodegenerative and psychiatric diseases, which makes them important targets for therapeutic intervention. iGluRs are divided into four major families, the AMPA, kainate, NMDA, and delta receptors. These receptors assemble as tetramers. The available crystal structures of the LBDs are very informative, but they can only provide a static view of the most stable conformational state of the system. We have designed a joint computational and experimental study to extend our knowledge of the atomic and molecular factors responsible for iGluR regulation. We will (1) characterize the process of ligand-binding for a set of ligands to the AMPA, kainate, and NMDA receptor LBDs using free energy computations and experimental measurements, (2) characterize LBD-LBD dimer rearrangements that underlie desensitization for the AMPA, kainate, and NMDA receptors using free energy computations, (3) measure solution X-ray scattering from LBD monomers, tethered dimers, and crosslinked tetramers to compare with the predicted conformational populations, and (4) try to crystallize crosslink-stabilized LBD tetramers and a stabilized LBD-pore assembly. PUBLIC HEALTH RELEVANCE: We propose a research project to understand the atomic and molecular factors that regulate "neuroreceptor" proteins called glutamate receptors. These proteins have key roles in neurodegenerative and psychiatric diseases. The research will help better understand the action of drugs targeting glutamate receptors.

描述（由申请人提供）：配体门控离子通道介导突触时的信息传输。这些通道的神经递质分子与配体结合结构域（LBD）的结合驱动了跨膜孔的打开，从而使阳离子越过细胞膜以触发突触后神经元中神经脉冲的产生。激动剂结合的位点通常远离跨膜孔，因此通道的激活必须通过在结合位点的构象变化的变构耦合到通道门的相应变化来介导。离子型谷氨酸受体离子通道（iGlurs）介导了大脑和脊髓中绝大多数突触的兴奋反应。越来越多的证据表明，iGlurs在各种神经退行性和精神病疾病中具有关键作用，这使其成为治疗干预的重要目标。 iglurs分为四个主要家庭，即AMPA，海藻酸盐，NMDA和三角洲受体。这些受体作为四聚体组装。 LBD的可用晶体结构非常有用，但是它们只能提供系统中最稳定的构象状态的静态视图。我们设计了一项联合计算和实验研究，以扩展我们对负责iGlur调节的原子和分子因素的了解。我们将（1）使用自由能量计算和实验测量值和实验测量值来表征一组配体的配体配体的配体结合过程，（2）表征LBD-LBD二聚体重排的特征，这些降低了AMPA，Kainate和NMDA的范围降低降低的降低范围，并使用Kainate和NMDA的范围（3）（3）（3）单体，束缚二聚体和交联的四聚体与预测的构象种群进行比较，（4）尝试结晶的交叉稳定的LBD四聚体和稳定的LBD孔组件。 公共卫生相关性：我们提出了一个研究项目，以了解调节称为谷氨酸受体的“神经受体”蛋白的原子和分子因素。这些蛋白质在神经退行性和精神疾病中具有关键作用。这项研究将有助于更好地了解针对谷氨酸受体的药物的作用。