Structure and Function of Pentameric Ligand-Gated Ion Channels

五聚体配体门控离子通道的结构和功能

基本信息

  • 批准号:
    10388455
  • 负责人:
  • 金额:
    $ 4.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-01-21 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract The overarching goal of the proposal is to determine the structural basis for allosteric mechanisms governing gating and modulation in pentameric ligand-gated ion channels (pLGIC). The pLGIC superfamily governs crucial physiological processes such as gastrointestinal functions, motor functions, and pain transmission. Aberrant channel functions are implicated in mood disorders, addiction, chronic pain, and cancer. Currently used therapeutic strategies suffer from our limited knowledge of the molecular details of pLGIC function, the origin of their functional diversity, and the downstream signaling events. Using single-particle cryo-EM, we recently solved structures of the full-length serotonin receptor (5HT3AR), a cationic pLGIC, in the resting state and two serotonin-activated conformations. Building on this technical advancement and further biochemical optimization, we aim to determine the conformational changes underlying gating and lipid modulation in the full- length homomeric and heteromeric receptors within the cationic 5-HT3R and anionic glycine receptor (GlyR) subfamilies. To achieve these goals we will use an approach that combines multidisciplinary techniques, including cryo-EM, pulsed-EPR, and electrophysiology. Specifically, we will determine high-resolution snapshots of pLGIC in multiple functional states, in modulator-bound conformations, in the presence of membrane lipid constituents, and in complex with intracellular-binding proteins. These structures will be validated and complemented with protein dynamic studies in a membrane environment and extensive functional analysis. Taken together, our proposed work is expected to provide molecular blueprints of the channel in physiologically relevant conformations for therapeutic targeting and unravel the molecular mechanisms underlying channel function. These findings will, in turn, pave the way for design of novel therapeutic agents that are safer and more effective.
项目总结/摘要 该提案的总体目标是确定变构机制的结构基础, 五聚体配体门控离子通道(pLGIC)中的门控和调节。pLGIC超家族控制着 生理过程,如胃肠功能、运动功能和疼痛传递。异常 通道功能与情绪障碍、成瘾、慢性疼痛和癌症有关。当前使用 治疗策略受到我们对pLGIC功能的分子细节, 它们的功能多样性和下游信号事件。使用单粒子冷冻EM,我们最近 全长5-羟色胺受体(5 HT 3AR),一种阳离子pLGIC,在静息状态和两种 阿托宁激活构象。基于这种技术进步和进一步的生物化学 优化,我们的目标是确定构象变化的基础门控和脂质调制的完整- 阳离子5-HT 3R和阴离子甘氨酸受体(GlyR)内的长度同聚和异聚受体 亚家族为了实现这些目标,我们将使用一种结合多学科技术的方法, 包括冷冻电镜脉冲EPR和电生理学具体来说,我们将确定高分辨率 pLGIC在多种功能状态下的快照,在调节剂结合构象中,在存在 膜脂质成分,并与细胞内结合蛋白复合。这些结构将 通过在膜环境中的蛋白质动态研究进行验证和补充, 分析.综上所述,我们提出的工作预计将提供分子蓝图的通道, 用于治疗靶向的生理学相关构象,并阐明分子机制 底层通道功能。这些发现将反过来为设计新的治疗药物铺平道路 更安全更有效

项目成果

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Sudha Chakrapani其他文献

Sudha Chakrapani的其他文献

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{{ truncateString('Sudha Chakrapani', 18)}}的其他基金

Acquisition of 200kV Glacios Cryo Transmission Electron Microscope
购置 200kV Glacios 冷冻透射电子显微镜
  • 批准号:
    10430469
  • 财政年份:
    2022
  • 资助金额:
    $ 4.19万
  • 项目类别:
Structure and Function of Pentameric Ligand-Gated Ion Channels
五聚体配体门控离子通道的结构和功能
  • 批准号:
    10317065
  • 财政年份:
    2020
  • 资助金额:
    $ 4.19万
  • 项目类别:
Structure and Function of Pentameric Ligand-Gated Ion Channels
五聚体配体门控离子通道的结构和功能
  • 批准号:
    10797535
  • 财政年份:
    2020
  • 资助金额:
    $ 4.19万
  • 项目类别:
Structure and Function of Pentameric Ligand-Gated Ion Channels
五聚体配体门控离子通道的结构和功能
  • 批准号:
    10543499
  • 财政年份:
    2020
  • 资助金额:
    $ 4.19万
  • 项目类别:
STRUCTURE, FUNCTION, AND MODULATION OF SERORTONIN (3A) RECEPTORS
5-羟色胺 (3A) 受体的结构、功能和调节
  • 批准号:
    9898063
  • 财政年份:
    2019
  • 资助金额:
    $ 4.19万
  • 项目类别:
Pulsed-Electron Paramagnetic Resonance Spectrometer for Distance Determination in Biological Macromolecules
用于生物大分子距离测定的脉冲电子顺磁共振波谱仪
  • 批准号:
    9492211
  • 财政年份:
    2018
  • 资助金额:
    $ 4.19万
  • 项目类别:
Molecular Mechanisms of Desensitization and Drug Modulation in Ligand-Gated Ion C
配体门控离子 C 脱敏和药物调节的分子机制
  • 批准号:
    8916155
  • 财政年份:
    2014
  • 资助金额:
    $ 4.19万
  • 项目类别:
Molecular Mechanisms of Desensitization and Drug Modulation in Ligand-Gated Ion Channels
配体门控离子通道脱敏和药物调节的分子机制
  • 批准号:
    9291772
  • 财政年份:
    2014
  • 资助金额:
    $ 4.19万
  • 项目类别:
Molecular Mechanisms of Desensitization and Drug Modulation in Ligand-Gated Ion C
配体门控离子 C 脱敏和药物调节的分子机制
  • 批准号:
    8757924
  • 财政年份:
    2014
  • 资助金额:
    $ 4.19万
  • 项目类别:

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