Dynamic Structures of Large and Flexible RNAs
大型且灵活的 RNA 的动态结构
基本信息
- 批准号:8190761
- 负责人:
- 金额:$ 22.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-30 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressArchitectureBase PairingBenchmarkingCerealsCharacteristicsChemicalsCodeComplexComputer SimulationComputing MethodologiesCrystallizationDataDatabasesDiseaseDrug Delivery SystemsElementsFingerprintFunctional RNAFutureGene Expression RegulationGenomeGenomicsGoalsGuanineHIVHigher Order Chromatin StructureIndividualInvestigationLeftLengthLettersLibrariesLigand BindingLigandsLinkMapsMethodologyMethodsModelingMolecularMolecular ConformationMolecular WeightMotionNMR SpectroscopyNatureNucleotidesPositioning AttributeProteinsRNARNA ConformationRNA SequencesRNA analysisResearchResolutionRoentgen RaysSamplingSolutionsSourceStructural ModelsStructureTestingThermodynamicsVisionX-Ray Crystallographyaptamerbasecombatdrug discoveryflexibilityinsightnovelresearch studythree dimensional structuretrend
项目摘要
DESCRIPTION (provided by applicant): Non-coding RNAs (ncRNAs) have emerged as abundant critical elements of the cellular machinery that are increasingly being targeted in drug discovery efforts. High-resolution 3D structure determination of ncRNAs provides the basis for understanding their functional mechanisms at the atomic level and for implementing structure-based approaches for drug discovery. However, RNA's unique characteristics continue to pose significant challenges to high-resolution structure determination by X-ray crystallography and NMR spectroscopy. The global structures of many ncRNAs are highly flexible and can therefore resist crystallization. Many ncRNAs have molecular weights that exceed the NMR limit of application (<100 nucleotides). This has made it necessary to excise individual RNA domains, suitable for characterization by X-ray and NMR, from their much larger context. This 'divide and conquer strategy' is often called into question by experiments showing that domains have overlapping functions and potentially associate to form higher order structures. By contrast, advances in computational and experimental methods are allowing determination of secondary structures for increasingly large and complex RNAs. Recently, we showed that topological constraints provide the missing link between RNA secondary structure and 3D global and dynamic adaptation. In this proposal, we propose to develop new computational methods that exploit these newly founded topological constraints to define global features of RNA structure based on secondary structure alone. By combining these global constraints with footprinting data and a new NMR chemical shift fingerprinting strategy for identifying tertiary motifs, we propose to develop a new paradigm for determining the 3D structural organization of large flexible RNAs. The methodology will be validated by determining the 3D conformation of the guanine sensing riboswitch aptamer domain in its stable ligand bound form and subsequently used to characterize the more flexible conformation of the domain in its ligand free form. Results will be used to test the hypothesis that topological constraints encoded in the unique three-way junction, and not long range loop-loop tertiary interactions, define the global structure of the aptamer domain giving rise to spatially tuned dynamics that are optimized for adaptive ligand binding.
PUBLIC HEALTH RELEVANCE: The proposed research will test the feasibility of developing a novel computational NMR method for determining structures of very large RNAs under solution conditions. The method obviates the need for crystallization or sharp NMR spectra, can be applied to RNA structures as large as 1000 nucleotides, and is expected to increase throughput over conventional methods by one-to-two orders of magnitude. This new paradigm for RNA structure determination will bring into the realm of application several modes of investigation that are currently impossible due to limitations in X-ray and NMR.
描述(由申请人提供):非编码rna (ncRNAs)已经成为细胞机制中丰富的关键元素,越来越多地成为药物发现工作的目标。ncrna的高分辨率3D结构测定为在原子水平上理解其功能机制和实施基于结构的药物发现方法提供了基础。然而,RNA的独特特性继续对x射线晶体学和核磁共振波谱的高分辨率结构测定构成重大挑战。许多ncrna的整体结构是高度灵活的,因此可以抵抗结晶。许多ncrna的分子量超过了核磁共振应用极限(<100个核苷酸)。这使得有必要从更大的背景中去除适合x射线和核磁共振表征的单个RNA结构域。这种“分而治之的策略”经常受到质疑,因为实验表明,区域具有重叠的功能,并可能形成更高阶的结构。相比之下,计算和实验方法的进步使得越来越大和复杂的rna的二级结构的确定成为可能。最近,我们发现拓扑约束提供了RNA二级结构与三维全局和动态适应之间缺失的一环。在本提案中,我们建议开发新的计算方法,利用这些新建立的拓扑约束来定义仅基于二级结构的RNA结构的全局特征。通过将这些全局约束与足迹数据和用于识别三级基序的新的NMR化学位移指纹识别策略相结合,我们建议开发一种用于确定大型柔性rna的3D结构组织的新范式。该方法将通过确定稳定配体结合形式的鸟嘌呤感应核素开关适体结构域的三维构象来验证,随后用于表征其自由配体形式的结构域的更灵活的构象。结果将用于验证这样的假设,即编码在独特的三向结中的拓扑约束,而不是长距离环-环三级相互作用,定义了适体域的全局结构,从而产生了空间调谐动力学,为自适应配体结合进行了优化。
项目成果
期刊论文数量(0)
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Hashim M Al-Hashimi其他文献
Characterizing the relative orientation and dynamics of RNA A-form helices using NMR residual dipolar couplings
利用核磁共振残余偶极耦合来表征 RNA A 型螺旋的相对取向和动力学
- DOI:
10.1038/nprot.2007.221 - 发表时间:
2007-06-14 - 期刊:
- 影响因子:16.000
- 作者:
Maximillian H Bailor;Catherine Musselman;Alexandar L Hansen;Kush Gulati;Dinshaw J Patel;Hashim M Al-Hashimi - 通讯作者:
Hashim M Al-Hashimi
Hashim M Al-Hashimi的其他文献
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{{ truncateString('Hashim M Al-Hashimi', 18)}}的其他基金
Development and application of a quantitive model for HIV-1 transcriptional activation driven by TAR RNA conformational dynamics
TAR RNA构象动力学驱动的HIV-1转录激活定量模型的开发和应用
- 批准号:
10750552 - 财政年份:2023
- 资助金额:
$ 22.76万 - 项目类别:
Fundamental Studies of RNA Conformational Thermodynamics
RNA构象热力学基础研究
- 批准号:
10281504 - 财政年份:2019
- 资助金额:
$ 22.76万 - 项目类别:
Fundamental Studies of RNA Conformational Thermodynamics
RNA构象热力学基础研究
- 批准号:
10491480 - 财政年份:2019
- 资助金额:
$ 22.76万 - 项目类别:
Fundamental Studies of RNA Conformational Thermodynamics
RNA构象热力学基础研究
- 批准号:
9924580 - 财政年份:2019
- 资助金额:
$ 22.76万 - 项目类别:
Fundamental Studies of RNA Conformational Thermodynamics
RNA构象热力学基础研究
- 批准号:
10557995 - 财政年份:2019
- 资助金额:
$ 22.76万 - 项目类别:
Fundamental Studies of RNA Conformational Thermodynamics
RNA构象热力学基础研究
- 批准号:
10348772 - 财政年份:2019
- 资助金额:
$ 22.76万 - 项目类别:
Biological Activity of Lead Compounds Targeting HIV-1 TAR RNA
靶向 HIV-1 TAR RNA 的先导化合物的生物活性
- 批准号:
8327894 - 财政年份:2012
- 资助金额:
$ 22.76万 - 项目类别:
Biological Activity of Lead Compounds Targeting HIV-1 TAR RNA
靶向 HIV-1 TAR RNA 的先导化合物的生物活性
- 批准号:
8508181 - 财政年份:2012
- 资助金额:
$ 22.76万 - 项目类别:
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