Structure and function of inositol triphosphate receptors
肌醇三磷酸受体的结构和功能
基本信息
- 批准号:10580508
- 负责人:
- 金额:$ 4.25万
- 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:2021-09-10 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffinityApoptosisAutoimmune DiseasesBindingBinding SitesBiological AssayCalciumCalcium SignalingCell divisionCryoelectron MicroscopyDataDevelopmentDiseaseDistantEndoplasmic ReticulumFluorescenceGene ExpressionGoalsGrowth FactorHormonesITPR1 geneImageInositolIon Channel GatingLearningLigandsMalignant NeoplasmsMediatingMembraneMemoryMetabolicMetabolic DiseasesMitochondriaMolecularNeurodegenerative DisordersNeurotransmittersPathogenesisPathologicPeptidesPharmacologyPhysiological ProcessesPropertyPublishingReceptor InhibitionRegulationResearchSignal TransductionSiteStructureSynaptic TransmissionTestingTherapeutic AgentsX-Ray Crystallographybasecell motilitycell typeinsightmutantnovelnovel therapeutic interventionnovel therapeuticsprotein aminoacid sequencereceptorsmall moleculetooltraffickingtripolyphosphate
项目摘要
PROJECT SUMMARY
Inositol 1,4,5-triphosphate receptors (IP3Rs) integrate diverse signals generated by hormones, growth
factors, neurotransmitters, and changes in metabolic state to modulate downstream signaling in all cell types.
IP3Rs are ligand-gated ion channels that are further regulated by allosteric and covalent mechanisms,
mediating Ca2+ release from the endoplasmic reticulum (ER). The resulting increases of cytoplasmic and
mitochondrial Ca2+ concentrations regulate many physiological processes (e.g., learning, memory, membrane
trafficking, synaptic transmission, secretion, motility, membrane excitability, gene expression, cell division, and
apoptosis). Furthermore, pathological dysregulation of IP3Rs and calcium signaling is implicated in cancer,
neurodegenerative, autoimmune, and metabolic diseases, making IP3Rs promising targets for treatment of
these diseases. Despite recent advances in structural studies, fundamental questions regarding the
mechanisms of ligand interactions and channel gating remain mostly unanswered, in part because of the large
size and complexity of IP3Rs and the limited availability of specific pharmacological tools.
In this proposal, we will (Aim 1) combine cryo-electron microscopy (cryo-EM) and X-ray crystallography
in conjunction with functional IP3R assays based on fluorescence-based calcium imaging to elucidate the
general themes of IP3R gating cycle and molecular basis for receptor inhibition by small molecules.
Our recently published data revealed that the IP3 binding site is occupied by a loop that we have
termed the self-binding peptide (SBP), which is located distantly in the primary sequence. We hypothesize that
the SBP is a novel regulatory site in IP3Rs that can modulate the apparent affinity for IP3, and thereby Ca2+
channel activity, and that the divergence of SBP sequences between IP3R subtypes contributes to their distinct
regulatory properties. We will perform (Aim 2) functional and structural studies on IP3R subtypes and SBP
mutants to test this hypothesis and identify the structural determinants of this interaction.
Completion of these aims will yield unparalleled mechanistic insight into IP3R gating and regulation,
potentially leading to the development of novel and specific pharmacological modulators of IP3Rs. In addition
to being used as a long-sought research tools to study IP3Rs, these compounds will serve as a starting point
for development of novel therapeutic approaches to treat diseases associated with aberrant IP3R activity.
项目摘要
肌醇1,4,5-三磷酸受体(IP 3Rs)整合了激素、生长激素和生长激素产生的多种信号。
因子、神经递质和代谢状态的变化来调节所有细胞类型中的下游信号传导。
IP 3R是配体门控离子通道,其进一步通过变构和共价机制调节,
介导Ca 2+从内质网(ER)释放。由此产生的细胞质和
线粒体Ca 2+浓度调节许多生理过程(例如,学习,记忆,膜
运输、突触传递、分泌、运动性、膜兴奋性、基因表达、细胞分裂和
凋亡)。此外,IP 3R和钙信号传导的病理性失调与癌症有关,
神经退行性疾病、自身免疫性疾病和代谢性疾病,使IP 3R成为治疗
这些疾病。尽管最近在结构研究方面取得了进展,
配体相互作用和通道门控的机制仍然没有得到解答,部分原因是大量的
IP 3R的规模和复杂性以及特定药理学工具的有限可用性。
在这个建议中,我们将(目标1)结合联合收割机低温电子显微镜(cryo-EM)和X射线晶体学
结合基于荧光钙成像的功能性IP 3R测定,以阐明
IP 3R门控循环的一般主题和小分子抑制受体的分子基础。
我们最近发表的数据显示,IP 3结合位点被一个环占据,
称为自结合肽(SBP),其位于一级序列中较远的位置。我们假设
SBP是IP 3R中的一个新的调节位点,可以调节IP 3的表观亲和力,从而调节Ca 2 +
通道活动,IP 3R亚型之间SBP序列的分歧有助于其不同的
监管属性。我们将对IP 3R亚型和SBP进行(目的2)功能和结构研究
突变体来测试这一假设,并确定这种相互作用的结构决定因素。
这些目标的完成将产生对IP 3R门控和监管的无与伦比的机械见解,
潜在地导致开发新的和特异性的IP 3R药理学调节剂。此外
这些化合物将作为研究IP 3R的一个起点,
用于开发新的治疗方法以治疗与异常IP 3R活性相关的疾病。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('ERKAN KARAKAS', 18)}}的其他基金
Structure and function of inositol triphosphate receptors
肌醇三磷酸受体的结构和功能
- 批准号:
10645116 - 财政年份:2021
- 资助金额:
$ 4.25万 - 项目类别:
Structure and function of inositol triphosphate receptors
肌醇三磷酸受体的结构和功能
- 批准号:
10365669 - 财政年份:2021
- 资助金额:
$ 4.25万 - 项目类别:
Structure and function of inositol triphosphate receptors
肌醇三磷酸受体的结构和功能
- 批准号:
10482419 - 财政年份:2021
- 资助金额:
$ 4.25万 - 项目类别:
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