Alpha7 Nicotinic Receptor: Structures and Coupling with Intracellular Proteins
Alpha7 烟碱受体:结构及其与细胞内蛋白质的偶联
基本信息
- 批准号:10393547
- 负责人:
- 金额:$ 47.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAddressAffectAgonistBindingBinding SitesBiophysicsBrainCell surfaceChimera organismCognitionCognitiveCouplingCryoelectron MicroscopyCrystallizationDevelopmentDiseaseDown-RegulationDrug TargetingElectron Spin Resonance SpectroscopyExtracellular DomainExtracellular StructureFoundationsGraphHumanImmune systemInvestigationIon Channel GatingLearningLeftLengthLigandsMediatingMemoryModelingMolecularMolecular ConformationNMR SpectroscopyNeurodegenerative DisordersNeuronsNicotinic ReceptorsOutcomes ResearchPlayProteinsRegulationResolutionRestRoentgen RaysRoleScaffolding ProteinSideSignal PathwaySignal TransductionSiteSolidStructureSubcellular structureSynapsesSynaptic plasticityTherapeuticTransmembrane DomainX-Ray Crystallographyalpha-bungarotoxin receptorbasedesensitizationdesignexperimental studyextracellularflexibilitynervous system disorderneurotransmissionnovelpositive allosteric modulatorrational designreceptorrestrainttargeted treatmenttherapeutic targettraffickingtransmission processtreatment strategy
项目摘要
Neuronal nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of pentameric ligand-gated ion
channels (pLGICs) that mediate fast neurotransmission and are therapeutic targets for various neurological
diseases and disorders. However, no single high-resolution structure has yet been determined for any
full-length nAChRs that contains the extracellular (ECD), transmembrane (TMD), and intracellular (ICD)
domains. Neither X-ray crystallography nor cryo-EM is suitable for resolving structures of the flexible ICD. Lines
of evidence suggest direct interactions between nAChRs and intracellular proteins implicated in synaptic
plasticity and cell signaling pathways, but few molecular details have been revealed due to the lack of
high-resolution structures of the ICD. Here, we propose to determine structures of α7nAChR, which is one of the
most abundant nAChR subtypes in the brain. We have successfully produced functional human full-length
α7nAChR and the TMD+ICD of α7nAChR along with substantial preliminary structural and functional results,
which built a solid foundation for carrying out structural investigations of α7nAChR. Using nuclear magnetic
resonance spectroscopy (NMR) and electron paramagnetic resonance (EPR), we will determine
atomic-resolution structures of the ICD. The ICD structures will be integrated with available structures of the
ECD and TMD, as well as with our newly collected structure restraints to generate structures for full-length
α7nAChR in the resting state. We will elucidate conformational changes underlying α7nAChR desensitization,
which is known to play a significant role in the synaptic control of action-potential transmission. Finally, we will
determine binding modes of α7nAChR networked with intracellular scaffold proteins that affect the distribution of
α7nAChR on the cell surface. The generated structures will provide useful information for developing treatment
strategies for diseases related to α7nAChR.
神经元烟碱乙酰胆碱受体(nAChRs)属于五聚体配体门控离子超家族
项目成果
期刊论文数量(3)
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 Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization.
- DOI:10.1021/acschemneuro.2c00783
- 发表时间:2023-03-15
- 期刊:
- 影响因子:5
- 作者:Bondarenko, Vasyl;Chen, Qiang;Singewald, Kevin;Haloi, Nandan;Tillman, Tommy S.;Howard, Rebecca J.;Lindahl, Erik;Xu, Yan;Tang, Pei
- 通讯作者:Tang, Pei
SARS-CoV-2 Spike Protein Downregulates Cell Surface α7nAChR through a Helical Motif in the Spike Neck.
- DOI:10.1021/acschemneuro.2c00610
- 发表时间:2023-02-15
- 期刊:
- 影响因子:5
- 作者:Tillman, Tommy S.;Chen, Qiang;Bondarenko, Vasyl;Coleman, Jonathan A.;Xu, Yan;Tang, Pei
- 通讯作者:Tang, Pei
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{{ truncateString('PEI TANG', 18)}}的其他基金
New Glycinergic Modulators as Potent Painkillers without Negative Psychoactive Effects - Supplement
新型甘氨酸调节剂作为有效的止痛药,没有负面的精神影响 - 补充
- 批准号:
10054996 - 财政年份:2019
- 资助金额:
$ 47.88万 - 项目类别:
Alpha7 Nicotinic Receptor: Structures and Coupling with Intracellular Proteins
Alpha7 烟碱受体:结构及其与细胞内蛋白质的偶联
- 批准号:
9915878 - 财政年份:2018
- 资助金额:
$ 47.88万 - 项目类别:
Alpha7 Nicotinic Receptor: Structures and Coupling with Intracellular Proteins
Alpha7 烟碱受体:结构及其与细胞内蛋白质的偶联
- 批准号:
10169782 - 财政年份:2018
- 资助金额:
$ 47.88万 - 项目类别:
X-RAY STRUCTURES OF PENTAMERIC ION CHANNELS IN THE ABSENCE AND PRESENCE OF ANEST
不存在和存在 Anest 时五聚体离子通道的 X 射线结构
- 批准号:
8362296 - 财政年份:2011
- 资助金额:
$ 47.88万 - 项目类别:
LARGE SCALE MD SIMULATIONS OF ANESTHETIC EFFECTS ON ION CHANNELS
离子通道麻醉效果的大规模 MD 模拟
- 批准号:
8364249 - 财政年份:2011
- 资助金额:
$ 47.88万 - 项目类别:
ANESTHETIC EFFECTS ON ION CHANNEL STRUCTURES & DYNAMICS
对离子通道结构的麻醉作用
- 批准号:
8127591 - 财政年份:2010
- 资助金额:
$ 47.88万 - 项目类别:
LARGE SCALE MD SIMULATIONS OF ANESTHETIC EFFECTS ON ION CHANNELS
离子通道麻醉效果的大规模 MD 模拟
- 批准号:
8171827 - 财政年份:2010
- 资助金额:
$ 47.88万 - 项目类别:
X-RAY STRUCTURES OF PENTAMERIC ION CHANNELS IN THE ABSENCE AND PRESENCE OF ANEST
不存在和存在 Anest 时五聚体离子通道的 X 射线结构
- 批准号:
8170297 - 财政年份:2010
- 资助金额:
$ 47.88万 - 项目类别:
LARGE SCALE MD SIMULATIONS OF ANESTHETIC EFFECTS ON ION CHANNELS
离子通道麻醉效果的大规模 MD 模拟
- 批准号:
7956089 - 财政年份:2009
- 资助金额:
$ 47.88万 - 项目类别:
LARGE SCALE MD SIMULATIONS OF ANESTHETIC EFFECTS ON ION CHANNELS
离子通道麻醉效果的大规模 MD 模拟
- 批准号:
7723136 - 财政年份:2008
- 资助金额:
$ 47.88万 - 项目类别:
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