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
- 来源:
- 关键词:AddressAgonistBindingBinding ProteinsBinding SitesBiochemicalBiological AssayCell membraneCentral Nervous System DiseasesClamsCommunicationComplementComplexCoupledCouplesCouplingCryoelectron MicroscopyCysteine-Rich DomainDefectDetergentsDiseaseDrug AddictionEnvironmentExtracellular DomainFamilyFunctional disorderG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGRM5 geneGTP-Binding ProteinsGlutamatesHeterotrimeric GTP-Binding ProteinsKnowledgeLengthLigand BindingLinkLipidsMapsMembraneMental DepressionMetabotropic Glutamate ReceptorsMicellesMolecularMolecular ConformationMutagenesisMutationNerve DegenerationNeuraxisNeurologicPainParkinson DiseasePharmacologyPhospholipidsPhysiologicalPreparationPropertyProteinsProtomerReceptor ActivationResolutionRoleSchizophreniaSideSignal TransductionSiteSpecificityStructureSynaptic TransmissionSynaptic plasticitySystemTestingTransmembrane DomainVenusWorkcombatcomputer studiesconformational conversiondesigndimerdrug discoveryextracellularflygamma-Aminobutyric Acidin vitro Assayinsightmetabotropic glutamate receptor 2molecular dynamicsnanodiskneuronal excitabilityneuropsychiatryneurotransmissionnovel therapeutic interventionprotein activationprotein complexreceptorreceptor couplingreceptor functionrelease of sequestered calcium ion into cytoplasmtherapeutic target
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
γ-氨基丁酸B受体和代谢性谷氨酸受体属于
G蛋白偶联受体C家族对神经元兴奋性、突触的重要调节作用
传递性和可塑性。中枢神经系统的许多紊乱与神经元兴奋性的改变有关
通过谷氨酸和氨基丁酸能系统。因此,mGluRs和GABABR一直是
巨大的药物发现努力,因为它们代表着治疗众多生理性疾病的主要治疗目标
功能障碍以及神经退行性疾病和神经精神疾病。除了典型的七个
跨膜螺旋(7TM)结构域,C家族GPCRs还包括一个大的细胞外‘金蝇捕蝇器’(VFT)
构成立体配基结合部位的结构域。配体与胞外VFT结构域的结合
触发VFT结构域从开放构象到闭合构象的大的构象变化。这只文蛤-
胞外区的壳状闭合导致受体参与和激活G蛋白。
跨膜结构域的细胞内侧,其机制尚不清楚。受体激活的G
然后,蛋白质发挥作用,增强或抑制二级信使信号级联。我们最近展示了
近全长mGluR5和GaABR在非活性和活性构象中的低温EM结构,揭示了
当配体与VFT结合时,7TM二聚体的组织结构发生了广泛的转变。尽管如此
随着研究的进展,关于跨细胞膜的变构通讯的几个关键问题仍然存在
C家族GPCRs,特别是G蛋白偶联和激活的机制。要解决这些问题
问题,我们建议获得mGluR2,mGluR5和GABABR及其同源物的复合体结构
G蛋白,并利用分子动力学模拟和诱变来探索结构洞察力
功能分析。这些受体-G蛋白复合体之间的相似和不同将使我们能够
对比和比较我们的发现,并检查G蛋白偶联和选择性的方面。总而言之,
这些研究将使我们能够创建一个详细的机制框架来理解C家族GPCRs
并将形成针对这些受体的新型治疗策略的设计基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Georgios Skiniotis其他文献
Georgios Skiniotis的其他文献
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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
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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
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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
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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
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