Ultraviolet Photodissociation Mass Spectrometry for Characterization of Biological Molecules
Ultraviolet Photodissociation Mass Spectrometry for Characterization of Biological Molecules
批准号:
10389836
负责人:
Jennifer S. Brodbelt
金额:
$10.04万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-01-01 至 2025-12-31
关键词:
Antibiotic ResistanceAreaBindingBiologicalBiomedical ResearchC-terminalCapillary ElectrophoresisCellsCellular MembraneChargeChemicalsCollaborationsComplexDiseaseDissociationElectronsGenetic TranscriptionGoalsHybridsIndividualLigandsLipidsMass Spectrum AnalysisMembrane ProteinsMethodsMicrobiologyModificationMolecularMolecular BiologyNucleic AcidsPatternPhosphorylationPost Translational Modification AnalysisPost-Translational Protein ProcessingPreparationProteinsRNA Polymerase IIResearchResearch SupportSamplingSolventsStructureStructure-Activity RelationshipTechnologybasedesigndisulfide bondfrontierfunctional outcomesinnovationinsightlipid Imacromolecular assemblymass spectrometernovel therapeuticsoxidationpathogenic bacteriaprogramsprotein complexprotein functiontandem mass spectrometryultraviolet
中文摘要
抽象的。了解脂质、蛋白质甚至更大的大分子组装体的功能
取决于破译单个分子的复杂结构,以及这些分子是如何
分子通常通过非共价相互作用的网络相互作用。为了进一步阐明
生物分子的组织和功能结果,需要新的方法来突破生物分子的极限
结构洞察力,提供更详细的整体化学信息,具有更高的灵敏度。临界
结构/功能之间的相互作用在许多生物学动机的问题中得到证明,
从了解致病菌产生抗生素耐药性的方式,到设计新的
选择性结合并抑制蛋白质靶点功能的药物。持续需要更大的
化学洞察力促使我的团队努力开发创新的质谱分析方法,
以前所未有的细节描述生物分子的结构,特别是脂质和蛋白质
这是本提案中的特色。我的研究计划的首要目标是发展国家的-
最先进的串联质谱技术,特别强调紫外光解离
(UVPD)和混合MS/MS方法,用于脂质、蛋白质和蛋白质复合物的结构解析。
这些新方法将被展示用于解决三个领域的挑战性问题。(1)脂质:(i)
分析病原菌的脂质及其抗生素抗性的特征,和(ii)结构
表征重塑过程中发生的脂质的不饱和、氧化和修饰,
细胞膜(2)蛋白质复合物:(i)蛋白质-配体复合物的表征,膜
蛋白质复合物、蛋白质/核酸复合物和大分子组装体,以及(ii)推进
毛细管电泳用于天然分离和相互作用组的探索。(3)翻译后
修饰:专注于解码RNA的C-末端结构域的磷酸化模式
调节转录的聚合酶II。这些高影响力的问题得到了许多支持,
与认识到前沿质量价值的微生物学和分子生物学小组合作
光谱分析战略,以提升生物医学研究。此补充支持购买
ExD电池可在现有质谱仪上实现基于电子的激活,
加快样品制备工作流程。ExD单元将支持研究领域2和3,
翻译后分析的电子捕获解离和电荷还原能力
蛋白质中二硫键的修饰和裂解。溶剂蒸发器将有助于
在所有三个研究领域准备样品。
英文摘要
Abstract. Understanding the functions of lipids, proteins and even larger macromolecular assemblies
depends on deciphering complex structures of individual molecules as well as decrypting how those
molecules interact, often via networks of non-covalent interactions. In order to advance the elucidation of
biomolecular organization and functional outcomes, new methods are needed to push the limits of
structural insight, providing more detailed holistic chemical information with greater sensitivity. The critical
interplay between structure/function is evidenced in numerous biologically-motivated problems, ranging
from understanding the ways that pathogenic bacteria develop antibiotic resistance to the design of new
drugs that selectively bind and inhibit the functions of protein targets. The ongoing need for even greater
chemical insight has motivated my group’s effort to develop innovative mass spectrometry methods to
characterize structures of biological molecules in unprecedented detail, especially lipids and proteins
which are featured in this proposal. The overarching goal of my research program is to develop state-of-
the-art tandem mass spectrometry technologies, particularly highlighting ultraviolet photodissociation
(UVPD) and hybrid MS/MS methods, for structural elucidation of lipids, proteins, and protein complexes.
These new methods will be showcased for solving challenging problems in three areas. (1) Lipids: (i)
profiling lipids of pathogenic bacteria and their signatures of antibiotic resistance, and (ii) structural
characterization of unsaturations, oxidations and modifications of lipids that occur during remodeling of
cellular membranes. (2) Protein complexes: (i) characterization of protein-ligand complexes, membrane
protein complexes, protein/nucleic acid complexes, and macromolecular assemblies, and (ii) advancing
capillary electrophoresis for native separations and exploration of the interactome. (3) Post-translational
modifications: focusing on decoding the phosphorylation patterns of the C-terminal domain of RNA
polymerase II which regulates transcription. These high impact problems are supported via numerous
collaborations with microbiology and molecular biology groups who recognize the value of frontier mass
spectrometry strategies for elevating biomedical research. This supplement supports acquisition of an
ExD cell to enable electron-based activation on existing mass spectrometers and a solvent evaporator to
accelerate sample preparation workflows. The ExD cell will support research areas 2 and 3 by allowing
electron capture dissociation and charge reduction capabilities for analysis of post-translational
modifications and cleavage of disulfide bonds in proteins. The solvent evaporator will facilitate
preparation of samples in all three research areas.
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会议论文
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Interpretation of the phosphorylation code of RNA polymerase II during eukaryotic transcription
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Interpretation of the phosphorylation code of RNA polymerase II during eukaryotic transcription
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UVPD Mass Spectrometry of Protein Complexes
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UVPD Mass Spectrometry of Protein Complexes
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Cracking the Ubiquitination Code by Top Down Mass Spectrometry
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Mapping the C Terminal Domain of RNA Polymerase II by UVPD Mass Spectrometry
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Mapping the C Terminal Domain of RNA Polymerase II by UVPD Mass Spectrometry
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