Structure-based functional analysis of RNA Polymerase

RNA 聚合酶基于结构的功能分析

• 批准号: 2884826
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2884826
• 关键词: Structure; based; functional; analysis; RNA

Research project summaryGene expression, the basic requirement for life, is considered the central dogma of molecular biology. This dogma describes the directional flow of genetic information from deoxyribonucleic acid (DNA) to ribonucleic acid (RNA) (transcription), to polypeptide chains (translation) that undergo post-translational modification to form functional proteins. Bacterial RNA polymerase (RNAp) is the central enzyme of gene expression whereby it accomplishes the polymerization of ribonucleoside triphosphates (NTPs). The catalytic core enzyme consists of five subunits In bacteria, RNAp, interacts with other cellular machineries, such as translation, DNA repair and replication. Bacterial RNAp is also a potent target for the development of antibacterials. RNAps in all living organisms are multisubunit, multidomain enzymes, and the functions of all the domains are still not well understood. Our laboratory solved structures of multisubunit RNAp from Escherichia coli (E.coli) stalled at a DNA lesion, which highlighted movements of some particular domains, which may be involved in signalling to translation and DNA repair machineries. Our laboratory also solved the structure of a small single-subunit relative of multi-subunit RNAps, which highlighted the structural conservation of domains of the active center, but divergence in the rest of the molecule, thus prompting the investigation of structure-based functional comparisons.Aims and objectivesThe overall aim of the project is to develop and characterize new inhibitors of RNAp. The project proposes to perform structure-based functional analysis of multisubunit RNAp and its single-subunit relative to bring insight into: the cross-talk between RNAp, ribosome, and DNA repair factors; functional conservation of the RNAp structure, principles of transcription inhibition by other cellular machineries and small molecules.The project will apply a wide arsenal of biochemical, microbiological, genetics, and structural biology techniques. We will use a range of known and new inhibitors of transcription as molecular probes of the functions of RNAps. Besides fundamental insights into the functions of bacterial RNAp, the project may lead to the discovery of new targets for inhibitors and novel candidate molecules for future development as antibacterials.KEYWORDSCell biology: understanding the fundamental properties, structure and function of the cell and how it responds to and influences its local environmentStructural biology and biophysics: understanding the atomic organisation of molecules and macromolecular complexes and the dynamic, functional relationships between these components in cells and biological systemsAntimicrobial resistance

研究项目摘要表达是生命的基本要求，被认为是分子生物学的核心教条。该教条描述了从脱氧核糖核酸（DNA）到核糖核酸（RNA）（转录）到多肽链（翻译）的遗传信息的方向流动，这些核酸（RNA）经过翻译后修饰以形成功能蛋白。细菌RNA聚合酶（RNAP）是基因表达的中心酶，通过它完成核糖核苷三磷酸（NTPS）的聚合。催化核心酶由细菌，RNAP中的五个亚基与其他细胞机制相互作用，例如翻译，DNA修复和复制。细菌RNAP也是开发抗菌物质的有效靶标。所有生物体中的RNAP都是多元素，多域酶，所有域的功能仍然尚不清楚。我们的实验室解决了来自大肠杆菌（E.COLI）的多生子RNAP的结构，该结构停滞在DNA病变处，这突出了某些特定域的运动，这些运动可能与信号传导到翻译和DNA修复机器有关。我们的实验室还解决了多生子rnaps的小单人亲戚的结构，该亲属强调了活跃中心域的结构保存，但在分子的其余部分中的差异，从而促使对基于结构的功能比较进行调查。MAIMS和对象维持该项目的整体目标是开发和形成新的InniN Innapors rnap ryap ryap。该项目提议对多亚基RNAP及其单单基因进行基于结构的功能分析，以使洞察力成为：RNAP，核糖体和DNA修复因子之间的串扰； RNAP结构的功能保护，其他细胞机械和小分子的转录抑制原理。该项目将应用广泛的生化，微生物，遗传学和结构生物学技术的武器。我们将使用一系列已知和新的转录抑制剂作为RNAP功能的分子探针。除了对细菌RNAP功能的基本见解外，该项目还可能导致发现抑制剂和新型候选分子的新靶标，以作为抗菌作用作为抗菌作用。KeywordScellBiology。复合物以及这些成分之间的动态，功能关系和生物系统抗药性