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：
9928579
负责人：
Georgios Skiniotis
金额：
$ 8.96万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9928579
关键词：
Adopted Agonist Alpha Particles Amino Acids 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 Crystallization Cysteine-Rich Domain Data Defect Detergents Drug Targeting Electron Spin Resonance Spectroscopy Environment Extracellular Domain Family Family member Fragile X Syndrome Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Glutamates 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 Pharmacology Physiological Population Protein Conformation Protein Engineering Proteins Receptor Signaling 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 conformational conversion conformer design dimer drug discovery experimental study extracellular fly glutamatergic signaling interest member metabotropic glutamate receptor 2 metabotropic glutamate receptor type 1 molecular dynamics nervous system disorder neuronal excitability neuropsychiatry novel therapeutics pain perception particle positive allosteric modulator presynaptic receptor reconstitution therapeutic target

项目摘要

Abstract Metabotropic Glutamate receptors (mGluRs) belong to the Family C of G-protein coupled receptors (GPCRs) and critically regulate 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.

抽象的代谢型谷氨酸受体 (mGluR) 属于 G 蛋白 C 家族偶联受体 (GPCR) 并严格调节神经元兴奋性、突触通过识别氨基酸和兴奋性来实现传输和可塑性神经递质谷氨酸。许多中枢神经系统疾病都与通过谷氨酸能系统改变神经元兴奋性。因此， mGluR 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疾病的主要治疗靶点功能障碍以及神经退行性和神经精神疾病。公寓 mGluRs 也来自原型七跨膜螺旋 (7TM) 结构域包括一个大的细胞外“捕蝇器”（VFT）结构域，它构成了谷氨酸结合位点和富含半胱氨酸的结构域 (CRD) 将 VFT 连接到 7TM。谷氨酸与细胞外 VFT 结构域的结合会触发大 VFT结构域从开放到封闭的构象变化构象。这种细胞外结构域的蛤壳状闭合导致细胞内侧 G 蛋白的受体结合和激活跨膜结构域。受体激活的 G 蛋白然后作用于增强或抑制第二信使信号级联。尽管密集努力，跨细胞膜的变构通讯机制由于缺乏完整的结构信息，mGluR 仍然是个谜。长度蛋白质。在这里我们建议应用单粒子冷冻电子显微镜（冷冻电镜）可视化，以表征结构 mGluR5 和 mGluR2 处于激活和失活状态以及复合物状态及其同源 G 蛋白。所得结构将用于分子动力学模拟旨在揭示构象的分子基础与信号激发或沉默相关的转变。鉴于 mGluR 是包括帕金森病在内的多种中枢神经系统疾病的重要药物靶点，脆性 X 综合征/自闭症谱系障碍、精神分裂症、认知、成瘾、抑郁、焦虑和痛苦，所获得的结果将产生深远的影响生物医学兴趣并将成为设计新型治疗方法的基础对抗神经系统疾病的策略。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structures of metabotropic GABAB receptor.

代谢型 GABAB 受体的结构。

DOI：
发表时间：
2020
期刊：
影响因子：
64.8
作者：
Papasergi;Robertson, Michael J;Seven, Alpay B;Panova, Ouliana;Mathiesen, Jesper M;Skiniotis, Georgios
通讯作者：
Skiniotis, Georgios

Structure of the M2 muscarinic receptor-β-arrestin complex in a lipid nanodisc.

脂质纳米盘中 M2 毒蕈碱受体-β-抑制蛋白复合物的结构。

DOI：
发表时间：
2020
期刊：
影响因子：
64.8
作者：
Staus, Dean P;Hu, Hongli;Robertson, Michael J;Kleinhenz, Alissa L W;Wingler, Laura M;Capel, William D;Latorraca, Naomi R;Lefkowitz, Robert J;Skiniotis, Georgios
通讯作者：
Skiniotis, Georgios

GemSpot: A Pipeline for Robust Modeling of Ligands into Cryo-EM Maps.

GemSpot：将配体稳健建模到冷冻电镜图谱中的管道。