CLC-2 voltage-gated chloride channel structure and ligand recognition
CLC-2电压门控氯离子通道结构和配体识别
基本信息
- 批准号:10391191
- 负责人:
- 金额:$ 43.29万
- 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:2021-09-30 至 2024-03-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsArchitectureAreaAttentionBiophysicsBrainCLC GeneCLC-2 proteinCalciumCationsChargeChemicalsChloride ChannelsChloridesClassificationComplexCryoelectron MicroscopyDataDependenceDetectionElectrophysiology (science)FamilyFluorescenceGoalsGreen Fluorescent ProteinsHuman bodyImageInvestigationIon ChannelIon Channel GatingIonsKidneyLabyrinthLigandsMembrane ProteinsMolecularMolecular ConformationMolecular Sieve ChromatographyMolecular StructureMovementNervous System PhysiologyNeuraxisNeurogliaNeuronsPlayPositioning AttributePotassiumPotassium ChannelPreparationProtocols documentationReportingResearchResearch Project GrantsResolutionRiskRoleSamplingShapesSignal TransductionSkeletal MuscleSodium ChannelStructureVariantbasecomputer studiesdesignfascinateinhibitor/antagonistinsightnanomolarneurophysiologynext generationprogramsreconstructionscreeningsmall moleculesmall molecule inhibitortoolvoltagevoltage gated channel
项目摘要
In the central nervous system (CNS), voltage-gated ion channels play central roles in shaping action-potential
firing. The cation-selective voltage-gated channels – sodium (Na+), potassium (K+), and calcium (Ca2+)) channels
– have received intense scrutiny over the past decades. In contrast, the chloride (Cl–)-selective voltage-gated
channel, CLC-2, is less well understood, despite its broad expression in neurons and glia throughout the CNS.
A complete understanding of CLC-2’s contribution to CNS function will include an understanding of CLC-2’s
molecular structure. Structurally, CLC channels possess a unique double-barreled architecture and operate
through distinct gating (opening/closing) mechanisms that differ markedly from those of the well-studied Na+, K+,
and Ca2+ channels. In addition to providing a critical framework for studying CLC-2 channel gating and
permeation mechanisms, another compelling rationale for determining the CLC-2 structure is its value for
understanding ligand interactions and guiding design of small-molecule probes. Such probes would be of great
value in investigations of CLC-2 neurophysiology. Accordingly, the goal of this R21 project is develop expression
and purification protocols for CLC-2 and to use cryo-electron microscopy to determine CLC-2 structures in the
absence and presence of the selective CLC-2 inhibitor AK-42.
在中枢神经系统(CNS)中,电压门控离子通道在塑造动作电位方面发挥着核心作用
击发阳离子选择性电压门控通道-钠(Na+)、钾(K+)和钙(Ca2+)通道
- 在过去的几十年里受到了严格的审查。相反,氯离子(Cl-)选择性电压门控
尽管CLC-2在整个CNS的神经元和神经胶质中广泛表达,但对CLC-2通道的了解较少。
对CLC-2对CNS功能的贡献的完整理解将包括对CLC-2的
分子结构在结构上,CLC渠道拥有独特的双管架构,
通过不同的门控(打开/关闭)机制,这些机制与研究充分的Na+,K+,
Ca2+通道除了为研究CLC-2通道门控提供关键框架外,
渗透机制,确定CLC-2结构的另一个令人信服的理由是它的价值,
理解配体相互作用和指导小分子探针的设计。这样的探测器将是伟大的
在CLC-2神经生理学研究中的价值。因此,本R21项目的目标是开发表达
和CLC-2的纯化方案,并使用冷冻电子显微镜来确定CLC-2在细胞中的结构。
不存在和存在选择性CLC-2抑制剂AK-42。
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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Merritt C Maduke其他文献
Merritt C Maduke的其他文献
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{{ truncateString('Merritt C Maduke', 18)}}的其他基金
Structure-based strategy for developing inhibitors of the kidney chloride channel CLC-Ka
基于结构的策略开发肾氯通道抑制剂 CLC-Ka
- 批准号:
10670342 - 财政年份:2021
- 资助金额:
$ 43.29万 - 项目类别:
Structure-based strategy for developing inhibitors of the kidney chloride channel CLC-Ka
基于结构的策略开发肾氯通道抑制剂 CLC-Ka
- 批准号:
10391185 - 财政年份:2021
- 资助金额:
$ 43.29万 - 项目类别:
Structure-based strategy for developing inhibitors of the kidney chloride channel CLC-Ka
基于结构的策略开发肾氯通道抑制剂 CLC-Ka
- 批准号:
10491286 - 财政年份:2021
- 资助金额:
$ 43.29万 - 项目类别:
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