Structural and Allosteric Mechanisms of mGluR Activation
mGluR 激活的结构和变构机制
基本信息
- 批准号:10679316
- 负责人:
- 金额:$ 4.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinityAgonistAlzheimer&aposs DiseaseAnxietyArchitectureBindingBiological AssayBrainBrain regionC-terminalCellsComplexCoupledCouplingCryoelectron MicroscopyCysteineCysteine-Rich DomainDataDimerizationDiseaseDrug TargetingExhibitsExtracellular DomainFamilyG-Protein-Coupled ReceptorsGTP-Binding ProteinsGlutamatesHeterodimerizationHeterogeneityHomoIn VitroKineticsLengthLigand BindingLigand Binding DomainLigandsMediatingMental DepressionMental disordersMetabotropic Glutamate ReceptorsModelingMolecularMolecular ConformationMolecular ProbesMutationNervous SystemNeurotransmittersPathway interactionsPatternPharmacologyPhysiologicalPlayPropertyPublishingReceptor ActivationReceptor SignalingReportingResolutionRoleSchizophreniaSequence HomologySeriesShapesStructureSynapsesSynaptic TransmissionSystemTechniquesTransmembrane DomainVisualizationWorkbiophysical analysisbiophysical techniquescomparativedimerextracellularimprovedinsightmetabotropic glutamate receptor 2metabotropic glutamate receptor 3nervous system disorderneurotransmitter releasenovelpatch clamppharmacologicpositive allosteric modulatorreceptorreceptor functionrecruitresponsetool
项目摘要
ABSTRACT
In the nervous system, G protein coupled receptors (GPCRs) serve to detect the precise spatial and temporal
pattern of neurotransmitter release to modulate synaptic transmission. The metabotropic glutamate receptors
(mGluRs) are family C GPCRs that sense the excitatory neurotransmitter glutamate. mGluRs are constitutive
dimers with a large extracellular ligand binding domain which is connected to a seven-helix transmembrane
domain via an intermediate cysteine-rich linker. There are eight mGluR subtypes, which are expressed in
overlapping regions of the brain and play distinct roles at the synapse. Additionally, mGluRs readily form
heterodimers, increasing the molecular diversity and functional complexity of this system. Recent breakthroughs
in cryogenic electron microscopy (cryo-EM) have led to full-length structures of mGluRs, providing an improved
understanding of the overall architecture of this receptor. However, these structures raise further questions
regarding the dynamic rearrangements that occur upon activation. While the extracellular domain is known to
undergo glutamate-induced rearrangements, how these conformational changes are coupled to yield activation
and G protein recruitment at the TMD remains to be defined. Additionally, how this coupling is tuned across
mGluR homo- and heterodimer subtypes to produce the observed differences in activation properties is
unknown. The group II mGluRs are ideal candidates for addressing these questions and are the focus of this
proposal. Group II mGluRs consist of mGluR2 and mGluR3, which have the highest sequence homology of all
mGluRs, yet still show distinct glutamate affinity, kinetics, and basal activity. Furthermore, mGluR2 and mGluR3
readily heterodimerize in the brain. In this proposal, I will use a combination of cryo-EM structural analysis and
functional assays in addition to subtype specific pharmacological compounds. Using these tools, I will probe the
conformational dynamics of group II mGluRs, with a focus on the allosteric mechanisms that couple ligand
binding to transmembrane domain activation. Together, this work will provide a high-resolution picture of
activation for mGluR homo- and heterodimers.
摘要
在神经系统中,G蛋白偶联受体(GPCRs)用于检测精确的空间和时间
调节突触传递的神经递质释放模式。代谢性谷氨酸受体
(MGluRs)是C家族GPCRs,感受兴奋性神经递质谷氨酸。MGluR是结构性的
具有连接到七螺旋跨膜的大的胞外配体结合域的二聚体
结构域通过一个富含半胱氨酸的中间连接子。有八个mGluR子类型,它们以
大脑的重叠区域,在突触上扮演着不同的角色。此外,mGluR很容易形成
异二聚体,增加了该体系的分子多样性和功能复杂性。最近的突破
在低温电子显微镜(Cryo-EM)中,已经导致了mGluRs的全长结构,提供了改进的
了解这个受体的整体架构。然而,这些结构引发了进一步的问题
关于在激活时发生的动态重排。而细胞外结构域已知为
经历谷氨酸诱导的重排,这些构象变化是如何耦合到产物激活的
G蛋白在TMD的募集仍有待确定。此外,这种耦合是如何调整的
导致观察到的活化性质差异的mGluR同源和异源二聚体亚型是
未知。第二组mGluR是解决这些问题的理想候选者,也是本报告的重点
求婚。第二组mGluRs由mGluR2和mGluR3组成,它们在所有序列中具有最高的同源性
MGluRs,但仍显示出明显的谷氨酸亲和力、动力学和基础活性。此外,mGluR2和mGluR3
很容易在大脑中形成异二聚体。在本提案中,我将结合使用低温电磁结构分析和
除亚型特定药理化合物外的功能分析。使用这些工具,我将探索
第二组mGluRs的构象动力学,重点是偶联配体的变构机制
结合到跨膜结构域的激活。总而言之,这项工作将提供一幅高分辨率的
激活mGluR同源和异源二聚体。
项目成果
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