Structural Basis of Signal Instigation Through Metabotropic Glutamate Receptors

通过代谢型谷氨酸受体信号激发的结构基础

基本信息

批准号：
9063626
负责人：
Georgios Skiniotis
金额：
$ 61.44万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9063626
关键词：
Adopted Agonist Anxiety Architecture Binding Binding Proteins Binding Sites Biochemical Biological Assay Cell membrane Cells Central Nervous System Diseases Characteristics Clams Cognition Combat Disorders Communication Complement Complex Coupled Coupling Cryoelectron Microscopy Cysteine-Rich Domain Data Defect Detergents Drug Targeting Electron Spin Resonance Spectroscopy Environment Excitatory Amino Acids Extracellular Domain Family Family member Fragile X Syndrome Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Glutamates Health Heterotrimeric GTP-Binding Proteins Human Genome Imagery Investigation Knowledge Learning Length Ligands Link Lipids Lipoproteins Measurement Membrane Membrane Proteins Memory Mental Depression Metabotropic Glutamate Receptors Methods Modeling Molecular Molecular Conformation Mutagenesis N-terminal Nerve Degeneration Nervous System Physiology Neuraxis Neurologic Neurotransmitters Pain Parkinson Disease Perception Physiological Population Protein Conformation Protein Engineering Proteins Resolution Role Schizophrenia Side Signal Transduction Structural Models Structure Synapses Synaptic Transmission Synaptic plasticity System Techniques Technology Transmembrane Domain Venus Work addiction autism spectrum disorder base conformational conversion conformer design dimer drug discovery extracellular fly glutamatergic signaling interest meetings member metabotropic glutamate receptor 2 metabotropic glutamate receptor type 1 molecular dynamics nervous system disorder neuronal excitability neuropsychiatry novel therapeutics particle positive allosteric modulator presynaptic receptor reconstitution research study therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Metabotropic Glutamate receptors (mGluRs) belong to the Family C of G-protein coupled receptors (GPCRs) and critically regulates neuronal excitability, synaptic transmission and plasticity through recognition of the amino acid and excitatory neurotransmitter glutamate. Many disorders of the CNS have been linked to alterations in neuronal excitability via the glutamatergic system. Accordingly, mGluRs have been the subject of an enormous drug discovery effort as they represent major therapeutic targets for treating numerous physiological dysfunctions and for neurodegenerative and neuropsychiatric conditions. Apart from the prototypical seven transmembrane helix (7TM) domain, mGluRs also include a large extracellular venus fly trap' (VFT) domain that constitutes the glutamate binding site and a cysteine rich domain (CRD) that links the VFT to the 7TM. Binding of glutamate to the extracellular VFT domain triggers a large conformational change in the VFT domains from an open to a closed conformation. This clam-shell like closure of the extracellular domain results in receptor engagement and activation of G-proteins on the intracellular side of the transmembrane domain. Receptor activated G proteins then act to either enhance or repress secondary messenger signaling cascades. Despite intensive efforts, the mechanism of allosteric communication across the cell membrane by the mGluRs remains enigmatic due to the lack of structural information on full- length proteins. Here we propose to apply single-particle cryo-electron microscopy (cryo-EM) visualization in order to characterize the structure of mGluR5 and mGluR2 in activated and inactivated states and also in complex with their cognate G-proteins. The obtained structures will be used for molecular dynamics simulations aiming to unravel the molecular basis for conformational transitions coupled to signal instigation or silencing. Given that mGluRs are important drug targets for several CNS conditions including Parkinson's disease, Fragile X syndrome/autism spectrum disorders, schizophrenia, cognition, addiction, depression, anxiety and pain, the results obtained will have profound biomedical interest and will form the basis for the design of novel therapeutic strategies against neurological disorders.

描述（由适用提供）：代谢型谷氨酸受体（MGLURS）属于G蛋白偶联受体（GPCRS）的家族C，并通过识别氨基酸和兴奋性神经释放剂Glutamate的识别来调节神经元令人兴奋，突触传播和可塑性。中枢神经系统的许多疾病与通过谷氨酸能系统的神经元令人兴奋的变化有关。根据MGLURS的说法，我们是巨大的药物发现工作的主题，因为它们代表了治疗多种身体功能障碍以及神经退行性和神经精神疾病的主要治疗靶标。除原型的七个跨膜螺旋（7TM）结构域外，MGLURS还包括一个构成谷氨酸结合位点和富含半胱氨酸的结构域（CRD）的大细胞外金星蝇陷阱'（VFT）结构域，该结构域将VFT连接起来。谷氨酸与细胞外VFT结构域的结合触发了VFT结构域中从开放到闭合构象中的大规模会议变化。这种蛤s壳像闭合细胞外结构域会导致受体的接合和激活G蛋白在跨膜结构域的细胞内侧。然后，受体激活的G蛋白起作用以增强或反映次级信使信号级联。尽管进行了大量努力，但由于缺乏有关全长蛋白的结构信息，MGLURS跨细胞膜变构的机制仍然存在。在这里，我们建议在激活和灭活状态中应用单粒子冷冻电子显微镜（Cryo-EM）可视化，以表征MGlUR5和MGLUR2的结构，并与其同源G蛋白相称。所获得的结构将用于分子动力学模拟，旨在揭示与信号启动或沉默的构象转变的分子基础。鉴于MGLUR是多种CNS疾病的重要药物靶标，包括帕金森氏病，脆弱的X综合征/自闭症谱系障碍，精神分裂症，认知，成瘾，抑郁症，焦虑和疼痛，所获得的结果将具有深远的生物医学兴趣，并将构成针对神经性疾病的新型治疗策略的基础。