Molecular mechanism of dimeric G protein-coupled receptor signaling
二聚体G蛋白偶联受体信号传导的分子机制
基本信息
- 批准号:10582139
- 负责人:
- 金额:$ 4.42万
- 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:2021-04-02 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnxietyBehavior DisordersBiological PhenomenaBloodBone DiseasesBrain DiseasesCalcium-Sensing ReceptorsCognitiveCouplingDefectDevelopmentDiseaseEpilepsyExtracellular DomainG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding ProteinsHomeostasisHumanLeadLengthLifeLigand BindingLigandsMediatingMembraneMetabolismMineralsMolecularNeuraxisProteinsReceptor ActivationResearchSignal TransductionStimulusStructural ModelsStructureSystemTherapeutic AgentsTransmembrane DomainWorkaddictiondesigndimerextracellularneurotransmissionnovel therapeuticsreceptorreceptor functionspasticitysynaptic inhibition
项目摘要
Summary
Our research seeks to uncover the molecular mechanisms of activation and modulation of two
dimeric G protein-coupled receptors (GPCRs), human GABAB receptor and human calcium-sensing
(CaS) receptor. The GABAB receptor is ubiquitous in the central nervous system, responsible for
mediating slow and prolonged synaptic inhibition. Defects in GABAB receptor have been implicated in
brain and behavioral disorders, including spasticity, epilepsy, addiction, and anxiety. CaS receptor
maintains a stable Ca2+ level in the blood. Abnormal activities of the CaS receptor are associated with a
vareity of Ca2+ homeostatic disorders including potentially life threatening hypercalcemic conditions.
Both receptors function as obligatory dimers and contain large extracellular domains that are
responsible for orthosteric ligand binding. Fundamental questions remain regarding how an
extracellular stimulus propagates a signal across the membrane through such a dimeric GPCR system.
Building on our structural models for the extracellular domains of each receptor, we plan to determine
full-length structures of these GPCRs, including their transmembrane domains, in multiple functional
states. For each receptor, we aim to address three main questions: (1) how the dimeric interactions
control receptor activation, (2) what the mode of coupling between each receptor and its cognitive G
protein is, and (3) how allosteric modulators and auxiliary proteins regulate receptor function. We will
combine structural and functional approaches to understand the molecular basis of ligand-induced
activation in each receptor system. Our findings will ultimately lead to the development of novel
therapeutics for treating diseases associated with the GABAB and CaS receptors.
概括
我们的研究旨在揭示两种物质激活和调节的分子机制
二聚体 G 蛋白偶联受体 (GPCR)、人类 GABAB 受体和人类钙感应
(CaS) 受体。 GABAB 受体普遍存在于中枢神经系统中,负责
介导缓慢且长时间的突触抑制。 GABAB 受体缺陷与
大脑和行为障碍,包括痉挛、癫痫、成瘾和焦虑。 CaS受体
维持血液中稳定的Ca2+水平。 CaS 受体的异常活性与
多种 Ca2+ 稳态紊乱,包括可能危及生命的高钙血症。
两种受体均作为必需二聚体发挥作用,并含有大的细胞外结构域
负责正位配体结合。关于如何
细胞外刺激通过这种二聚体 GPCR 系统跨膜传播信号。
基于每个受体胞外域的结构模型,我们计划确定
这些 GPCR 的全长结构,包括其跨膜结构域,具有多种功能
州。对于每个受体,我们的目标是解决三个主要问题:(1)二聚体如何相互作用
控制受体激活,(2)每个受体与其认知G之间的耦合模式是什么
(3)变构调节剂和辅助蛋白如何调节受体功能。我们将
结合结构和功能方法来了解配体诱导的分子基础
每个受体系统的激活。我们的发现最终将导致新颖的开发
用于治疗与 GABAB 和 CaS 受体相关的疾病的疗法。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('QING R FAN', 18)}}的其他基金
Molecular mechanism of dimeric G protein-coupled receptor signaling
二聚体G蛋白偶联受体信号传导的分子机制
- 批准号:
10207012 - 财政年份:2021
- 资助金额:
$ 4.42万 - 项目类别:
Molecular mechanism of dimeric G protein-coupled receptor signaling
二聚体G蛋白偶联受体信号传导的分子机制
- 批准号:
10382430 - 财政年份:2021
- 资助金额:
$ 4.42万 - 项目类别:
Molecular mechanism of dimeric G protein-coupled receptor signaling
二聚体G蛋白偶联受体信号传导的分子机制
- 批准号:
10588166 - 财政年份:2021
- 资助金额:
$ 4.42万 - 项目类别:
Mechanism of activation and modulation in human GABA(B) receptor
人 GABA(B) 受体的激活和调节机制
- 批准号:
9982345 - 财政年份:2018
- 资助金额:
$ 4.42万 - 项目类别:
Mechanism of activation and modulation in human GABA(B) receptor
人 GABA(B) 受体的激活和调节机制
- 批准号:
10224896 - 财政年份:2018
- 资助金额:
$ 4.42万 - 项目类别:
Mechanism of activation and modulation in human GABA(B) receptor
人 GABA(B) 受体的激活和调节机制
- 批准号:
10388693 - 财政年份:2018
- 资助金额:
$ 4.42万 - 项目类别:
Structural studies of human extracellular calcium-sensing receptor
人细胞外钙敏感受体的结构研究
- 批准号:
9293333 - 财政年份:2015
- 资助金额:
$ 4.42万 - 项目类别:
Structural Studies of Metabotropic GABA Receptors
代谢型 GABA 受体的结构研究
- 批准号:
7915372 - 财政年份:2009
- 资助金额:
$ 4.42万 - 项目类别:
Structural Studies of Metabotropic GABA Receptors
代谢型 GABA 受体的结构研究
- 批准号:
8118530 - 财政年份:2009
- 资助金额:
$ 4.42万 - 项目类别:
Structural Studies of Metabotropic GABA Receptors
代谢型 GABA 受体的结构研究
- 批准号:
8513349 - 财政年份:2009
- 资助金额:
$ 4.42万 - 项目类别:
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