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（由申请人提供）：代谢型谷氨酸受体（mGluR）属于 G 蛋白偶联受体（GPCR）C 家族，通过识别氨基酸和兴奋性神经递质谷氨酸来严格调节神经元兴奋性、突触传递和可塑性。中枢神经系统的变化与谷氨酸能系统神经元兴奋性的改变有关。 mGluRs 一直是巨大药物发现工作的主题，因为它们代表了治疗多种生理功能障碍以及神经退行性和神经精神疾病的主要治疗靶点，除了典型的七跨膜螺旋 (7TM) 结构域外，mGluR 还包括一个大型细胞外捕蝇器。 VFT）结构域，构成谷氨酸结合位点，以及将VFT与7TM连接的富含半胱氨酸结构域（CRD），使谷氨酸与细胞外结合。 VFT 结构域引发 VFT 结构域从开放构象到闭合构象的巨大构象变化，这种胞外结构域的蛤壳状闭合导致受体接合并激活跨膜结构域的细胞内侧的 G 蛋白。然后，G 蛋白会增强或抑制次级信使信号级联反应，尽管付出了巨大的努力，但由于缺乏全长结构信息，mGluR 跨细胞膜的变构通讯机制仍然是个谜。在这里，我们建议应用单颗粒冷冻电子显微镜 (cryo-EM) 可视化来表征激活和失活状态下的 mGluR5 和 mGluR2 的结构以及与其同源 G 蛋白的复合物。鉴于 mGluR 是多种中枢神经系统疾病的重要药物靶标，可用于分子动力学模拟，旨在揭示与信号激发或沉默相结合的构象转变的分子基础。包括帕金森病、脆性X综合征/自闭症谱系障碍、精神分裂症、认知、成瘾、抑郁、焦虑和疼痛，所获得的结果将具有深远的生物医学意义，并将成为设计针对神经系统疾病的新型治疗策略的基础。