BioEmPiRe; Accessing uncharted but essential landscapes to biological machineries by pulse EPR

生物EmPiRe；

• 批准号: BB/W019795/2
• 负责人: Christos Pliotas
• 金额: $ 126.01万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW019795%2F2
• 关键词: BioEmPiRe; Accessing; uncharted; but; essential

To understand biological processes at a molecular detail one needs to capture and visualize proteins in action. Modern structural biology methods such as X-ray crystallography and cryo-electron microscopy (CryoEM) could provide static high-resolution snapshots of protein structures, but they are unable to capture proteins in motion to reveal dynamic function. The new state-of-the-art electron paramagnetic resonance (EPR) spectrometer in Leeds will be capable of extracting accurate distances between pairs of unpaired electrons engineered on protein sites and thus acting as a molecular nanoscale-ruler. The accurate measurement of such distances over a protein's functional cycle will thereby enable the elucidation of fundamental biological processes. Pulsed EPR is a powerful method in modern biomolecular research and has seen tremendous technical advances over the last 10 years with sensitivity increasing by more than an order of magnitude. As a network of protein structural molecular biologists in Leeds (including several leading EPR specialists), consider PELDOR as a key approach in the future of biosciences. We have a very large base of users in Leeds, nationally (Imperial, King's, Glasgow, St Andrews) and abroad (EU, Australia and India) and an unmatched variety of fundamental biological systems with representative proteins across all kingdoms of life. These proteins are involved in a wide range of disease-related biological mechanisms from cancer and neurodegeneration to antimicrobial resistance and metabolism. Novel information for fundamental biological machineries in molecular detail and currently inaccessible by other methods, would be first revealed by the new EPR spectrometer. Our investigators, collaborators and industrial partners come from a wide range of national and international institutions. We have an extensive track record in the field of EPR and biological and medical sciences and anticipate this installation will substantially increase the UK's capability and reputation in biological EPR worldwide. Our business case will ensure sustainability for the Leeds-based centre and will serve the North East and other Universities as demonstrated by our list of groups and investigators actively supporting BioEmPiRe. The position of an EPR staff scientist will be secured for an initial period of two years through a contribution by the University of Leeds. In addition, intended location will be fully refurbished and a chiller will be purchased to enable the optimal installation and operation of the spectrometer. The instrument will be part of the UK academic and industrial networks further ensuring sustainability. These upgrades will allow the UK to remain internationally competitive and to continue developing and applying the EPR methodology to important problems across the biosciences.

要了解分子细节的生物过程，需要捕获和可视化作用中的蛋白质。现代结构生物学方法，例如X射线晶体学和冷冻电子显微镜（冷冻）可以提供蛋白质结构的静态高分辨率快照，但它们无法捕获运动中的蛋白质以揭示动态功能。 LEEDS中新的最先进的电子顺磁共振（EPR）光谱仪将能够在蛋白质位点设计的几对未配对电子之间提取准确的距离，从而充当分子纳米级持有仪。在蛋白质的功能周期中，准确测量此类距离将使基本生物学过程能够阐明。脉冲EPR是现代生物分子研究中的一种强大方法，在过去的10年中，敏感性提高了不仅仅是数量级的巨大技术进步。作为利兹蛋白结构分子生物学家的网络（包括几位领先的EPR专家），将Peldor视为生物科学未来的关键方法。我们在利兹，全国（帝国，国王，格拉斯哥，圣安德鲁斯）以及国外（欧盟，澳大利亚和印度）的使用者中拥有大量的用户，以及在生活的所有王国中都有代表性蛋白质的无与伦比的基本生物系统。这些蛋白质参与了从癌症和神经退行性变化到抗菌耐药性和代谢的广泛的与疾病相关的生物学机制。新的EPR光谱仪首先揭示了基本生物机械基础生物机械的新信息，目前无法通过其他方法访问。我们的调查人员，合作者和工业伙伴来自各种国家和国际机构。我们在EPR，生物学和医学科学领域拥有广泛的记录，并预测，这一装置将大大提高英国在全球生物EPR中的能力和声誉。我们的业务案例将确保利兹中心的可持续性，并将为东北和其他大学提供服务，这是我们的团体和调查人员积极支持生物Empire的列表所证明的。通过利兹大学的贡献，将在两年内确保EPR员工科学家的职位。此外，预期位置将进行全面翻新，并将购买冷却器，以实现光谱仪的最佳安装和操作。该工具将成为英国学术和工业网络的一部分，进一步确保可持续性。这些升级将使英国能够保持国际竞争力，并继续开发和应用EPR方法，以应对整个生物科学的重要问题。

项目成果

Darobactin B Stabilises a Lateral-Closed Conformation of the BAM Complex in E. coli Cells

Darobactin B 稳定大肠杆菌细胞中 BAM 复合物的横向闭合构象

• DOI: 10.1002/ange.202218783
• 发表时间: 2023
• 期刊: Angewandte Chemie
• 作者: Haysom S