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

基本信息

批准号：
7949990
负责人：
ALBERT Y LAU
金额：
$ 3.27万
依托单位：
UNIVERSITY OF CHICAGO
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：
2010-09-03 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7949990
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 Investigation Ion Channel Joints Knowledge Ligand Binding Ligand Binding Domain Ligands Measurement Measures Mediating Mental disorders Methodology Microscopic Modeling Molecular Molecular Conformation N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Nerve Degeneration 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 conformational conversion crosslink delta opioid receptor desensitization design dimer flexibility kainate monomer nervous system disorder novel postsynaptic public health relevance receptor receptor function research study response simulation

项目摘要

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处的信息传递。神经递质分子与这些通道的配体结合域 (LBD) 的结合驱动跨膜孔的打开，允许阳离子流过细胞膜，从而触发突触后神经元中神经冲动的产生。激动剂结合位点通常远离跨膜孔，因此通道的激活必须通过结合位点处的构象变化与通道门处的相应变化的变构耦合来介导。离子型谷氨酸受体离子通道 (iGluR) 介导大脑和脊髓绝大多数突触的兴奋反应。越来越多的证据表明，iGluR 在多种神经退行性疾病和精神疾病中发挥着关键作用，这使得它们成为治疗干预的重要目标。 iGluR 分为四个主要家族：AMPA、红藻氨酸、NMDA 和 δ 受体。这些受体组装成四聚体。 LBD 的可用晶体结构信息非常丰富，但它们只能提供系统最稳定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 iGluR 调节的原子和分子因素的了解。我们将 (1) 使用自由能计算和实验测量来表征一组配体与 AMPA、红藻氨酸和 NMDA 受体 LBD 的配体结合过程，(2) 表征作为 AMPA 脱敏基础的 LBD-LBD 二聚体重排、红藻氨酸盐和 NMDA 受体，使用自由能计算，(3) 测量 LBD 单体、束缚二聚体和交联四聚体的溶液 X 射线散射，以与预测的构象群体进行比较，并且（4）尝试结晶交联稳定的LBD四聚体和稳定的LBD孔组装体。公共健康相关性：我们提出了一个研究项目，以了解调节“神经受体”蛋白质（称为谷氨酸受体）的原子和分子因素。这些蛋白质在神经退行性疾病和精神疾病中发挥着关键作用。该研究将有助于更好地了解针对谷氨酸受体的药物的作用。