Examining G-quadruplex metal site heterogeneity and the influence of peptide binding using 2D IR spectroscopy
使用 2D 红外光谱检查 G-四链体金属位点异质性和肽结合的影响
基本信息
- 批准号:10730921
- 负责人:
- 金额:$ 37.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAffinityAlkali MetalsBase SequenceBehaviorBindingBinding ProteinsBiological ProcessCationsCell physiologyCircular DichroismComplexCoupledCouplingDNADataDiseaseDrug DesignDrug ModulationDrug TargetingElectrostaticsElementsEnvironmentEventFrequenciesFutureG-QuartetsGenetic TranscriptionGoalsGuanineHeterogeneityHumanHydrogen BondingIn VitroIndividualIon ExchangeIonsIsotope LabelingIsotopesLabelLocationMapsMass Spectrum AnalysisMeasurementMeasuresMetalsMethodsModelingMolecularNucleic AcidsOligonucleotidesPeptidesPharmaceutical PreparationsPlayPropertyProteinsResearchResolutionRoleSiteSpatial DistributionSpectrum AnalysisStructureSystemTechniquesTelomere-Binding ProteinsTestingTherapeutic AgentsTrainingVariantbasecareercell growth regulationchromophoreexperimental studygraduate studenthelicasehuman diseaseimaging probeimprovedin vivoinfrared spectroscopyinsightmembermolecular imagingmultidisciplinarypromoterprotein complexsimulationstudent trainingtooltraining opportunitytranscription factortwo-dimensionalundergraduate studentunnatural amino acidsvirtual
项目摘要
PROJECT SUMMARY
G-quadruplexes (G4s) are four-stranded nucleic acid motifs that have been implicated in a diverse array of
biological functions and diseases and have emerged as attractive targets for drug design. The coordination of
alkali metal ions (e.g., K+, Na+) to guanine C6=O carbonyls is a critical factor in their assembly and stabilization,
and thus, is likely to influence interactions with proteins that recognize and remodel G4s to perform regulatory
functions. Although thousands of G4s have been structurally characterized and there is extensive understanding
of their in vitro folding/unfolding behaviors, the overall lack of molecular-level data about their interactions with
proteins results in a major gap in understanding if/how metal binding and protein interactions are coupled.
Ultrafast two-dimensional infrared (2D IR) spectroscopy is a powerful probe of local electrostatics, vibrational
coupling, and femtosecond-picosecond fluctuations. Together with site specific labeling, it has been applied to
many proteins to discover subtle variations in binding interactions that are often hidden from high-resolution
techniques. We have recently developed 2D IR methods for structural analysis of G4s and showed that isotope
editing can detect variations in metal site occupancy, plasticity, and dynamics. Combined, 2D IR provides a
useful method to probe the interplay between metal coordination, folding/unfolding, and protein binding in G4s.
This proposal expands on established methods in two Specific Aims. In the first Aim, we use 2D IR and
isotope editing to test the hypothesis that native state dynamics and C6=O bond frequencies correlate with the
global stability of a G4, sequential assembly and disassembly mechanisms, and native state metal exchange
rates. In the second Aim, we examine the interactions of G4s with peptides derived from proteins that either
stabilize or unwind G4s and test the hypothesis that peptide (protein) binding biases the metal stabilized G4 core
in the direction of unfolding or folding depending on function. If this study is successful, it will provide fundamental
insight into the physicochemical properties of G4s and may provide clues for how to target G4:protein complexes
with drugs and imaging probes. The project also provides an interdisciplinary training environment for graduate
and undergraduate students that will prepare them for future careers in research.
项目概要
G-四链体 (G4) 是四链核酸基序,涉及多种
生物功能和疾病已成为药物设计的有吸引力的目标。的协调
碱金属离子(例如 K+、Na+)与鸟嘌呤 C6=O 羰基的结合是其组装和稳定的关键因素,
因此,可能会影响与识别和重塑 G4 来执行调节的蛋白质的相互作用
功能。尽管已经对数千个 G4 进行了结构表征并且有了广泛的了解
它们的体外折叠/展开行为,总体缺乏关于它们与
蛋白质导致在理解金属结合和蛋白质相互作用是否/如何耦合方面存在重大差距。
超快二维红外 (2D IR) 光谱是局部静电学、振动学的强大探针
耦合和飞秒-皮秒波动。与特定地点的标签一起,它已被应用于
许多蛋白质发现结合相互作用的微妙变化,这些变化通常在高分辨率下被隐藏
技术。我们最近开发了用于 G4s 结构分析的 2D IR 方法,并表明同位素
编辑可以检测金属位点占用、可塑性和动力学的变化。结合起来,2D IR 提供了
探测 G4 中金属配位、折叠/解折叠和蛋白质结合之间相互作用的有用方法。
该提案扩展了两个具体目标的既定方法。在第一个目标中,我们使用 2D IR 和
同位素编辑来测试本机态动力学和 C6=O 键频率与
G4 的全局稳定性、顺序组装和拆卸机制以及本机状态金属交换
费率。在第二个目标中,我们研究了 G4 与衍生自蛋白质的肽的相互作用,这些蛋白质要么
稳定或解开 G4 并测试肽(蛋白质)结合偏向金属稳定的 G4 核心的假设
根据功能,展开或折叠的方向。如果这项研究成功,它将提供基础
深入了解 G4 的理化特性,并可能为如何靶向 G4:蛋白质复合物提供线索
用药物和成像探针。该项目还为研究生提供跨学科的培训环境
以及本科生,为他们未来的研究职业做好准备。
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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{{ truncateString('Sean D Moran', 18)}}的其他基金
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