Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
基本信息
- 批准号:7563283
- 负责人:
- 金额:$ 29.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-04-01 至 2011-02-28
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseArchitectureBiochemicalBiochemistryBiologicalBiological ProcessBiophysicsCell DeathCockayne SyndromeComplexDNADNA DamageDNA RepairDefectDiseaseERCC3 geneElectronsEukaryotaEventFigs - dietaryGene MutationGenetic TranscriptionGerm-Line MutationHomologous GeneHumanIn VitroInheritedKnowledgeLaboratoriesLeadLengthLinkMalignant NeoplasmsMapsMediatingMental RetardationMicroscopicMolecularMolecular ConformationMolecular StructureMutationNerve DegenerationNucleotide Excision RepairOutcomePathway interactionsPatientsPhenotypePredispositionPremature aging syndromeProcessProteinsRepair ComplexResolutionRoleSkin CancerSpecificityStructureStructure-Activity RelationshipSyndromeTestingTranscription InitiationTranscription-Coupled RepairTrichothiodystrophyXPGC proteinXeroderma Pigmentosumbasecancer cellclinical phenotypedisease phenotypedisease-causing mutationhelicasehuman diseasein vivomutantprotein protein interactionrepairedresearch studystructural biologytranscription factor TFIIH
项目摘要
Hereditary mutations in the DNA helicases XPB and XPD lead to human diseases with different
phenotypes reflecting increased cancers or increased cell death: xeroderma pigmentosum (XP), XP-
linked Cockayne syndrome (CS), and trichothiodystrophy (TTD). These diseases reflect the disruption of
different cellular pathways: Defective nucleotide-excision repair (NER) results in XP, perturbed
transcription-coupled repair (TCR) leads to CS, and transcription abnormalities combined with defective
NER cause TTD. In humans, XPB and XPD helicases are part of the ten subunit TFIIH
transcription/repair complex, but disease-causing mutations cluster in XPB and particularly XPD rather
than in the other TFIIH proteins, excepting TFB5, so these XP helicases appear key to controlling
coordination of transcription and repair. Furthermore, the repair proteins XPG and CSB interact with the
XP helicases in TCR. However, there is little knowledge at the molecular level about XPB and XPD,
their helicase and repair activities, or their interactions with TFB5, CSB and XPG. We aim to
understand the molecular features underlying the specificity, activity, conformational controls and
pathway coordination by the XPB and XPD helicases. Our hypothesis is that well-defined architectures,
conformational states, and molecular interfaces of XPB and XPD helicases provide critical controls for
transcription, NER, and TCR. We furthermore propose that characterizations of these features and their
disruption by disease-causing mutations will provide a molecular basis to directly connect the inherited
gene mutations to disease phenotypes. To test this, we herein propose to integrate structural and
biophysical experiments (Tainer laboratory) with biochemical and biological experiments (Cooper
laboratory). Our experiments on XPB and XPD domains and full-length proteins, their archaeal
homologues, and their key assemblies will establish molecular architectures, conformational switching
mechanisms, and allosteric interactions. We expect to characterize a prototypical set of helicase
structures, their complexes with DNA and with protein partners, and to define the key interactions for
their activities. The anticipated outcome of the proposed cross-disciplinary experiments is a molecular
picture of the protein-DNA complexes, protein-protein interactions and functional states that orchestrate
transcription and repair events mediated by XPB and XPD as components of TFIIH. These results will
help provide a detailed molecular understanding of the processes that underlie the cancer and cell
death disease phenotypes associated with XPB, XPD, TFB5, CSB and XPG patient mutations.
DNA解旋酶XPB和XPD中的遗传突变导致具有不同的DNA水平的人类疾病。
反映癌症增加或细胞死亡增加的表型:着色性干皮病(XP),XP-
连锁Cockayne综合征(CS)和甲状腺营养不良(TTD)。这些疾病反映了
不同的细胞途径:缺陷核苷酸切除修复(NER)导致XP,干扰
转录偶联修复(TCR)导致CS,而转录异常与缺陷性
NER导致TTD。在人类中,XPB和XPD解旋酶是TFIIH十个亚基的一部分,
转录/修复复合物,但致病突变聚集在XPB,特别是XPD,而不是
比在其他TFIIH蛋白质中,除了TFB 5,所以这些XP解旋酶似乎是控制TFIIH蛋白质的关键。
转录和修复的协调。此外,修复蛋白XPG和CSB与蛋白质相互作用。
TCR中的XP解旋酶。然而,关于XPB和XPD在分子水平上的知识很少,
它们的解旋酶和修复活性,或它们与TFB 5、CSB和XPG的相互作用。我们的目标是
了解潜在的特异性,活性,构象控制和
通过XPB和XPD解旋酶的途径协调。我们的假设是,定义良好的架构,
XPB和XPD解旋酶的构象状态和分子界面提供了关键的控制,
转录、NER和TCR。我们还提出,这些特征的表征及其
致病突变的破坏将提供一个分子基础,
基因突变到疾病表型。为了验证这一点,我们在此建议将结构和
生物物理实验(泰纳实验室)与生物化学和生物学实验(库珀
实验室)。我们对XPB和XPD结构域以及全长蛋白质、其古细菌的实验,
同源物及其关键组件将建立分子结构,构象转换,
机制和变构相互作用。我们希望能描述一组典型的解旋酶
结构,它们与DNA和蛋白质伴侣的复合物,并定义关键的相互作用,
他们的活动。所提出的跨学科实验的预期结果是一种分子
蛋白质-DNA复合物的图片,蛋白质-蛋白质相互作用和协调的功能状态
作为TFIIH组分的XPB和XPD介导的转录和修复事件。这些结果将
帮助提供对癌症和细胞基础过程的详细分子理解
与XPB、XPD、TFB 5、CSB和XPG患者突变相关的死亡疾病表型。
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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John A. Tainer其他文献
Molecular model of TFIIH recruitment to the transcription-coupled repair machinery
TFIIH 招募到转录偶联修复机制的分子模型
- DOI:
10.1038/s41467-025-57593-0 - 发表时间:
2025-03-08 - 期刊:
- 影响因子:15.700
- 作者:
Tanmoy Paul;Chunli Yan;Jina Yu;Susan E. Tsutakawa;John A. Tainer;Dong Wang;Ivaylo Ivanov - 通讯作者:
Ivaylo Ivanov
DNA repair without flipping out
DNA 修复而不抓狂
- DOI:
10.1038/nature15646 - 发表时间:
2015-10-28 - 期刊:
- 影响因子:48.500
- 作者:
David S. Shin;John A. Tainer - 通讯作者:
John A. Tainer
A prismatic view of the epigenetic-metabolic regulatory axis in breast cancer therapy resistance
乳腺癌治疗耐药中表观遗传-代谢调节轴的棱柱形视图
- DOI:
10.1038/s41388-024-03054-9 - 发表时间:
2024-05-08 - 期刊:
- 影响因子:7.300
- 作者:
Chandrima Das;Apoorva Bhattacharya;Swagata Adhikari;Atanu Mondal;Payel Mondal;Santanu Adhikary;Siddhartha Roy;Kenneth Ramos;Kamlesh K. Yadav;John A. Tainer;Tej K. Pandita - 通讯作者:
Tej K. Pandita
Proteines de fusion ciblees par clycosaminoglycane, leurs conception, construction et compositions
糖胺聚糖融合蛋白、概念、结构和成分
- DOI:
- 发表时间:
1991 - 期刊:
- 影响因子:0
- 作者:
John A. Tainer;Leslie A. Kuhn;Maurice Boissinot;Cindy L. Fisher;Hans E. Parge;J. H. Griffin;Guy Mullenbach;Robert A. Hallewell - 通讯作者:
Robert A. Hallewell
Multiscale Modeling of PCNA - Ubiquitin Interactions
- DOI:
10.1016/j.bpj.2009.12.2087 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Ivaylo Ivanov;Adam Van Wynsberghe;John A. Tainer;J. Andrew McCammon - 通讯作者:
J. Andrew McCammon
John A. Tainer的其他文献
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{{ truncateString('John A. Tainer', 18)}}的其他基金
Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)
DNA 修复复合物结构集成的介观和纳米技术 (MANTIS-DRC)
- 批准号:
10687040 - 财政年份:2018
- 资助金额:
$ 29.84万 - 项目类别:
Mesocale And Nanoscale Technologies Integrated by Structures for DNA Repair Complexes (MANTIS-DRC)
DNA 修复复合物结构集成的介观和纳米技术 (MANTIS-DRC)
- 批准号:
10251045 - 财政年份:2018
- 资助金额:
$ 29.84万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8840824 - 财政年份:2012
- 资助金额:
$ 29.84万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8656719 - 财政年份:2012
- 资助金额:
$ 29.84万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8469234 - 财政年份:2012
- 资助金额:
$ 29.84万 - 项目类别:
MINOS (Macromolecular Insights on Nucleic acids Optimized by Scattering)
MINOS(通过散射优化核酸的大分子见解)
- 批准号:
8475491 - 财政年份:2012
- 资助金额:
$ 29.84万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
8212285 - 财政年份:2006
- 资助金额:
$ 29.84万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
7767763 - 财政年份:2006
- 资助金额:
$ 29.84万 - 项目类别:
Structural Biology of XPB and XPD Helicases
XPB 和 XPD 解旋酶的结构生物学
- 批准号:
7096103 - 财政年份:2006
- 资助金额:
$ 29.84万 - 项目类别:
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