Structural Basis of Signal Instigation Through Family C GPCRs

通过 C 族 GPCR 激发信号的结构基础

基本信息

  • 批准号:
    10456480
  • 负责人:
  • 金额:
    $ 5.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-03-15 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

Abstract The γ-aminobutyric acid B receptor (GABABR) and the metabotropic glutamate receptors (mGluRs) belong to the Family C of G protein coupled receptors (GPCRs) and critically regulate neuronal excitability, synaptic transmission and plasticity. Many disorders of the CNS have been linked to alterations in neuronal excitability via the glutamatergic and GABAergic system. Accordingly, mGluRs and GABABR 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, Family C GPCRs also include a large extracellular ‘venus fly trap’ (VFT) domain that constitutes the orthosteric ligand binding site. Binding of ligand 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 with a mechanism that remains unclear. Receptor activated G proteins then act to either enhance or repress secondary messenger signaling cascades. We recently showed cryoEM structures of near-full length mGluR5 and GABABR in inactive and active conformations, revealing extensive transitions in the organization of the 7TM dimer upon ligand binding to the VFT. Notwithstanding this progress, several key questions remain regarding the allosteric communication across the cell membrane by Family C GPCRs, and particularly the mechanism of G protein coupling and activation. To address these questions, we propose to obtain the structures of mGluR2, mGluR5 and GABABR in complex with their cognate G proteins and probe the structural insights using molecular dynamics simulations and mutagenesis coupled to functional assays. The similarities and differences amongst these receptor-G protein complexes will allow us to contrast and compare our findings and examine aspects of G protein coupling and selectivity. Collectively, these studies will enable us to create a detailed mechanistic framework to understand Family C GPCR signaling and will form the basis for the design of novel therapeutic strategies targeting these receptors.
摘要

项目成果

期刊论文数量(0)
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Georgios Skiniotis其他文献

Georgios Skiniotis的其他文献

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{{ truncateString('Georgios Skiniotis', 18)}}的其他基金

Mechanistic Basis of Calcium Sensing Receptor Signaling
钙传感受体信号传导的机制基础
  • 批准号:
    10467554
  • 财政年份:
    2022
  • 资助金额:
    $ 5.84万
  • 项目类别:
Mechanistic Basis of Calcium Sensing Receptor Signaling
钙传感受体信号传导的机制基础
  • 批准号:
    10596176
  • 财政年份:
    2022
  • 资助金额:
    $ 5.84万
  • 项目类别:
Structural Basis of Signal Instigation Through Family C GPCRs
通过 C 族 GPCR 激发信号的结构基础
  • 批准号:
    10767205
  • 财政年份:
    2021
  • 资助金额:
    $ 5.84万
  • 项目类别:
Structural Basis of Signal Instigation Through Family C GPCRs
通过 C 族 GPCR 激发信号的结构基础
  • 批准号:
    10583455
  • 财政年份:
    2021
  • 资助金额:
    $ 5.84万
  • 项目类别:
Structural Basis of Signal Instigation Through Family C GPCRs
通过 C 族 GPCR 激发信号的结构基础
  • 批准号:
    10368110
  • 财政年份:
    2021
  • 资助金额:
    $ 5.84万
  • 项目类别:
Structural Basis of Signal Instigation Through Family C GPCRs
通过 C 族 GPCR 激发信号的结构基础
  • 批准号:
    10456501
  • 财政年份:
    2021
  • 资助金额:
    $ 5.84万
  • 项目类别:
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
  • 批准号:
    9928579
  • 财政年份:
    2019
  • 资助金额:
    $ 5.84万
  • 项目类别:
Architectural Basis of Leptin Transmembrane Signaling
瘦素跨膜信号传导的结构基础
  • 批准号:
    9486433
  • 财政年份:
    2017
  • 资助金额:
    $ 5.84万
  • 项目类别:
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
  • 批准号:
    9266501
  • 财政年份:
    2015
  • 资助金额:
    $ 5.84万
  • 项目类别:
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
  • 批准号:
    9063626
  • 财政年份:
    2015
  • 资助金额:
    $ 5.84万
  • 项目类别:

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Agonist-GPR119-Gs复合物的结构生物学研究
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