Structure and Function of AMPA subtype ionotropic glutamate receptors
AMPA 亚型离子型谷氨酸受体的结构和功能
基本信息
- 批准号:10437793
- 负责人:
- 金额:$ 50.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-30 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAdamantaneAlzheimer&aposs DiseaseAnimal ModelAntiepileptic AgentsBehaviorBinding SitesBiochemicalBiophysicsCell LineCellsColorComplementComplexCryoelectron MicroscopyCrystallizationDementiaDevelopmentDiseaseDrug DesignDrug TargetingElectrophysiology (science)EpilepsyEpileptogenesisEukaryotic CellFamilyFluorescenceFutureGlutamate ReceptorGoalsHomoIndividualInsectaIon ChannelIschemiaKnowledgeLearningLengthMapsMediatingMemoryMental disordersMethodologyMethodsModelingModernizationMolecularMolecular StructureMonitorMutagenesisNeuraxisNeurodegenerative DisordersPharmaceutical PreparationsPharmacotherapyPlayPolyaminesPositioning AttributePrimary Lateral SclerosisProteinsProtocols documentationRegulationResearchResolutionSeizuresStructural ModelsStructureTechniquesTestingTherapeuticToxinTransfectionViralantagonistbasebiophysical modelcognitive processdesigndrug candidatedrug developmentdrug testingexperimental studyexpression vectorhuman diseasehuman modelimprovedin silicoinhibitorion channel blockerkinetic modelmolecular dynamicsmolecular modelingnervous system disorderneurotransmissionnext generationnovel therapeuticspatch clamppromoterreceptor expressionreceptor structure functionscaffoldsmall molecule
项目摘要
AMPA receptors mediate fast excitatory neurotransmission, contribute to high cognitive processes such as
learning and memory and are implicated in numerous psychiatric and neurodegenerative diseases. In
particular, AMPA receptors play a key role in epileptogenesis and seizure spread and, thus, have recently
emerged as one of the most promising targets for epilepsy therapy. However, development of drugs targeting
AMPA receptors has been stalled because of the lack of knowledge about AMPA receptor structure and
function. For example, only structures of homotetrameric intact AMPA receptors have been determined, while
the overwhelming majority of AMPA receptors in the central nervous system are heterotetramers. A number of
noncompetitive inhibitors and ion channel blockers have been identified as promising candidates for drug
development but structural mechanisms of their action on AMPA receptors remain largely unexplored. This
missing information is absolutely critical for the future structure-based rational drug design. We plan to study
structure and function of AMPA receptors using a combination of biophysical and biochemical approaches,
including modern crystallographic and cryo-electron microscopy (cryo-EM) techniques, fluorescence-based
methods, electrophysiology, kinetic and molecular modeling. Our specific aims are to (1) obtain structures of
heteromeric AMPA receptors, (2) establish the molecular mechanism of noncompetitive inhibition, and (3) build
a structural model of ion channel block. To reach our goals, we will optimize AMPA receptor constructs for
crystallization and cryo-EM experiments, develop protocols of their expression and purification and solve
structures of heterotetrameric AMPA receptors and AMPA receptors in complex with noncompetitive inhibitors
and ion channel blockers. To improve our structural models, we will use new methods of structural refinement
combined with molecular dynamics (MD) simulations. We will also test our models using a combination of
experimental and in silico mutagenesis, whole-cell patch-clamp recordings and MD simulations. To understand
the molecular mechanisms of AMPA receptor heteromeric assembly, noncompetitive inhibition and ion channel
block, we will perform extensive MD simulations of homo- and heteromeric AMPA receptors in different
activation states and in the presence or absence of noncompetitive inhibitors and ion channel blockers. We will
combine the results of structural, computational, functional and mutagenesis experiments to propose molecular
models of AMPA receptor heteromeric assembly, noncompetitive inhibition and ion channel block. Reaching
our research goals will provide molecular level knowledge essential to greatly facilitate design of new
molecules that will have a potential to become safe and more efficacious drugs to treat epilepsy and other
disorders related to excitatory neurotransmission.
AMPA 受体介导快速兴奋性神经传递,有助于高级认知过程,例如
学习和记忆,并与许多精神疾病和神经退行性疾病有关。在
特别是,AMPA 受体在癫痫发生和癫痫发作扩散中发挥着关键作用,因此最近
成为癫痫治疗最有希望的靶点之一。然而,靶向药物的开发
由于缺乏对 AMPA 受体结构和功能的了解,AMPA 受体的研究一直停滞不前。
功能。例如,仅确定了同源四聚体完整 AMPA 受体的结构,而
中枢神经系统中绝大多数 AMPA 受体是异四聚体。一些
非竞争性抑制剂和离子通道阻滞剂已被确定为有希望的候选药物
但它们对 AMPA 受体作用的结构机制在很大程度上仍未被探索。这
缺失的信息对于未来基于结构的合理药物设计绝对至关重要。我们计划学习
结合生物物理和生化方法研究 AMPA 受体的结构和功能,
包括现代晶体学和冷冻电子显微镜 (cryo-EM) 技术、基于荧光的
方法、电生理学、动力学和分子建模。我们的具体目标是(1)获得以下结构:
异聚 AMPA 受体,(2) 建立非竞争性抑制的分子机制,(3) 构建
离子通道块的结构模型。为了实现我们的目标,我们将优化 AMPA 受体结构
结晶和冷冻电镜实验,开发其表达和纯化方案并解决
异四聚体 AMPA 受体和与非竞争性抑制剂复合的 AMPA 受体的结构
和离子通道阻滞剂。为了改进我们的结构模型,我们将使用新的结构细化方法
与分子动力学(MD)模拟相结合。我们还将使用以下组合来测试我们的模型
实验和计算机诱变、全细胞膜片钳记录和 MD 模拟。要了解
AMPA受体异聚组装、非竞争性抑制和离子通道的分子机制
块,我们将对不同的同聚和异聚 AMPA 受体进行广泛的 MD 模拟
激活状态以及存在或不存在非竞争性抑制剂和离子通道阻滞剂的情况。我们将
结合结构、计算、功能和诱变实验的结果,提出分子
AMPA 受体异聚体组装、非竞争性抑制和离子通道阻断模型。达到
我们的研究目标将提供必要的分子水平知识,以极大地促进新产品的设计
这些分子将有可能成为治疗癫痫和其他疾病的安全且更有效的药物
与兴奋性神经传递有关的疾病。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structural mechanism of TRPM7 channel regulation by intracellular magnesium.
- DOI:10.1007/s00018-022-04192-7
- 发表时间:2022-04-07
- 期刊:
- 影响因子:0
- 作者:Schmidt E;Narangoda C;Nörenberg W;Egawa M;Rössig A;Leonhardt M;Schaefer M;Zierler S;Kurnikova MG;Gudermann T;Chubanov V
- 通讯作者:Chubanov V
AMPA Receptor Noncompetitive Inhibitors Occupy a Promiscuous Binding Site
- DOI:10.1021/acschemneuro.9b00344
- 发表时间:2019-11-01
- 期刊:
- 影响因子:5
- 作者:Narangoda, Chamali;Sakipov, Serzhan N.;Kurnikova, Maria G.
- 通讯作者:Kurnikova, Maria G.
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MARIA G KURNIKOVA其他文献
MARIA G KURNIKOVA的其他文献
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{{ truncateString('MARIA G KURNIKOVA', 18)}}的其他基金
Structure and Function of AMPA subtype ionotropic glutamate receptors
AMPA 亚型离子型谷氨酸受体的结构和功能
- 批准号:
10197227 - 财政年份:2013
- 资助金额:
$ 50.1万 - 项目类别:
MOLECULAR DYNAMIC SIMULATION OF THE INTERACTION OF THE ADAPTER WITH THE GENETIC
适配器与遗传相互作用的分子动力学模拟
- 批准号:
8364196 - 财政年份:2011
- 资助金额:
$ 50.1万 - 项目类别:
Approaches to Modeling Key Elements in Glutamate Receptors Activation Mechanism
谷氨酸受体激活机制关键元件的建模方法
- 批准号:
8321974 - 财政年份:2011
- 资助金额:
$ 50.1万 - 项目类别:
Approaches to Modeling Key Elements in Glutamate Receptors Activation Mechanism
谷氨酸受体激活机制关键元件的建模方法
- 批准号:
8244174 - 财政年份:2011
- 资助金额:
$ 50.1万 - 项目类别:
DYNAMICS AND RIGIDITY/FLEXIBILITY OF THERMOPHILIC AND MESOPHILIC PROTEINS
嗜热和嗜温蛋白质的动力学和刚性/柔性
- 批准号:
8171774 - 财政年份:2010
- 资助金额:
$ 50.1万 - 项目类别:
MOLECULAR DYNAMIC SIMULATION OF THE INTERACTION OF THE ADAPTER WITH THE GENETIC
适配器与遗传相互作用的分子动力学模拟
- 批准号:
8171767 - 财政年份:2010
- 资助金额:
$ 50.1万 - 项目类别:
ENERGETICS OF THE CLEFT CLOSING TRANSITION AND GLUTAMATE BINDING IN THE GLUTAMA
谷氨酸中裂隙闭合转变和谷氨酸结合的能量
- 批准号:
7956194 - 财政年份:2009
- 资助金额:
$ 50.1万 - 项目类别:
DYNAMICS AND RIGIDITY/FLEXIBILITY OF THERMOPHILIC AND MESOPHILIC PROTEINS
嗜热和嗜温蛋白质的动力学和刚性/柔性
- 批准号:
7956304 - 财政年份:2009
- 资助金额:
$ 50.1万 - 项目类别:
MOLECULAR DYNAMIC SIMULATION OF THE INTERACTION OF THE ADAPTER WITH THE GENETIC
适配器与遗传相互作用的分子动力学模拟
- 批准号:
7956083 - 财政年份:2009
- 资助金额:
$ 50.1万 - 项目类别:
ENERGETICS OF THE CLEFT CLOSING TRANSITION AND GLUTAMATE BINDING IN THE GLUTAMA
谷氨酸中裂隙闭合转变和谷氨酸结合的能量
- 批准号:
7723333 - 财政年份:2008
- 资助金额:
$ 50.1万 - 项目类别:
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