Structural and functional studies of the IkappaB kinase (IKK) complex
IkappaB 激酶 (IKK) 复合物的结构和功能研究
基本信息
- 批准号:7879303
- 负责人:
- 金额:$ 37.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-06-25 至 2014-05-31
- 项目状态:已结题
- 来源:
- 关键词:AttentionBaculovirusesBindingBiochemicalBiologicalBiological Response ModifiersC-terminalCalorimetryCell NucleusCellsComplement Factor BComplexCrystallizationDataDiseaseElectron MicroscopyEnzyme KineticsFamilyGenetic TranscriptionHTATIP2 geneHeartHelix-Loop-Helix MotifsHereditary DiseaseHumanHuman Herpesvirus 8IkappaB kinaseInflammatoryInflammatory ResponseInsectaInterleukin-1 ReceptorsLengthLeucine ZippersLigationLinkMalignant NeoplasmsMediatingMolecularMolecular ConformationMutationN-terminalNuclearOncogene ProteinsPaperPathway interactionsPhosphorylationPhosphotransferasesPolyubiquitinPolyubiquitinationProteinsPublishingReceptors, Antigen, B-CellReportingSeriesSignal TransductionStructureSurface Plasmon ResonanceSystemT-Cell ReceptorTitrationsToll-like receptorsTumor Necrosis Factor ReceptorTumor Necrosis Factor-alphaTumor Necrosis FactorsUbiquitinVirus DiseasesZinc Fingersbasecytokinedesigndimergenetic regulatory proteinhuman diseaseimage reconstructioninhibitor/antagonistlight scatteringmembermicrobialmolecular massmulticatalytic endopeptidase complexmutantprotein protein interactionpublic health relevancereceptorresponsetherapeutic targettranscription factor
项目摘要
DESCRIPTION (provided by applicant): Transcription factors in the nuclear factor ?B (NF-?B) family are evolutionarily conserved master regulators of immune and inflammatory responses. They are activated in response to ligation of many receptors including T-cell receptors, B-cell receptors, members of the tumor necrosis factor (TNF) receptor superfamily and the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) superfamily. The I?B kinase (IKK), comprising IKKa and IKK¿, is at the heart of NF-?B activation and mediates two NF-?B activation pathways. The canonical NF-?B pathway is triggered by microbial and viral infections and pro-inflammatory cytokines and is dependent on IKK¿ phosphorylation and activation. The alternative pathway is triggered by certain members of the TNF cytokine family and selectively activates IKKa. Activated IKK phosphorylates I?Bs, leading to their polyubiquitination and subsequent degradation by the proteasome. The freed NF-?B dimers translocate to the nucleus to mediate transcription. Because of its importance in NF-?B activation, IKK, especially IKK¿, has become a potential therapeutic target for many human diseases. The regulatory protein NEMO (also known as IKK? or FIP-3) interacts with IKKa and/or IKK¿ to form the IKKa, IKK¿ or IKKa/¿ holo-complex. The intact IKK¿ holo-complex is approximately 700-900kD in molecular mass containing multiple copies of IKK2 and NEMO. IKKa and IKK¿ both contain the following conserved recognizable domains: a kinase domain (KD), a leucine zipper domain (LZ), a helix loop helix domain (HLH) and a C-terminal NEMO-binding domain (NBD). NEMO contains an N-terminal kinase-binding domain (KBD), a minimal oligomerization domain (MOD) that is also the ubiquitin binding domain (UBD) and a C-terminal zinc finger domain (ZF). IKK and NF-?B signaling has attracted tremendous attention with more than 30,000 papers published on the subject. Despite the biological importance, not a single successful structure determination has been reported on IKK, an indication on the difficulty of the project. To elucidate the molecular basis of IKK function and to assist the discovery of IKK inhibitors, we propose a series of structural and functional studies on IKK, in particular, IKK¿ and its regulatory protein NEMO. Public Health Relevance: The I?B kinase (IKK) is at the heart of NF-?B activation and a potential therapeutic target for many human diseases. The proposal seeks structural studies of IKK, which will enhance our understanding on the molecular basis of IKK function. In addition, the proposed studies will provide a structural basis for discovery and optimization of IKK inhibitors in the treatment of inflammatory diseases and cancer.
描述(申请人提供):核因子B(核因子B)家族中的转录因子是进化上保守的免疫和炎症反应的主要调节因子。它们在T细胞受体、B细胞受体、肿瘤坏死因子受体超家族成员和Toll样受体/白介素1受体超家族成员的连接下被激活。I?B激酶(IKK)由IKA和IKK组成,是核因子-β活化的核心,介导了两条核因子-β激活途径。典型的NF-B途径由微生物和病毒感染以及促炎细胞因子触发,依赖于IKK的磷酸化和激活。另一种途径由肿瘤坏死因子家族的某些成员触发,并选择性地激活Ikka。活化的IKK使I?B磷酸化,导致其多泛素化,并随后被蛋白酶体降解。释放出来的核因子-?B二聚体转位到细胞核以调节转录。由于其在核因子-β活化中的重要作用,IKK,尤其是IKK,已成为许多人类疾病的潜在治疗靶点。调节蛋白Nemo(也被称为ikk?或FIP-3)与Ikka和/或Ikk相互作用形成Ikka、Ikk或Ikka/全息复合体。完整的IKK?全息复合体的分子质量约为700-900kD,含有IKK2和NEMO的多个拷贝。Ikka和ikk都含有以下保守的可识别结构域:激酶域(Kd)、亮氨酸拉链结构域(LZ)、螺旋环螺旋结构域(HLH)和C末端Nemo结合结构域(NBD)。NEMO含有一个N末端的激酶结合域(KBD)、一个同时也是泛素结合域(UBD)的最小寡聚结构域(MOD)和一个C末端的锌指结构域(ZF)。IKK和核因子?B信号已经引起了极大的关注,发表了30,000多篇关于这一主题的论文。尽管在生物学上具有重要意义,但在IKK上还没有一个成功的结构确定的报告,这表明了该项目的困难。为了阐明IKK功能的分子基础,并帮助发现IKK抑制剂,我们提出了一系列关于IKK的结构和功能的研究,特别是IKK及其调控蛋白NEMO。公共卫生相关性:I?B激酶(IKK)是核因子-B激活的核心,也是许多人类疾病的潜在治疗靶点。该提案旨在对IKK的结构进行研究,这将加深我们对IKK功能的分子基础的理解。此外,拟议的研究将为发现和优化IKK抑制剂在治疗炎症性疾病和癌症中的作用提供结构基础。
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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Hao Wu其他文献
Hao Wu的其他文献
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Elucidating the structural mechanism of pore formation by the (GSDM) Gasdermin family
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