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

生物EmPiRe；

• 批准号: BB/W019795/1
• 负责人: Christos Pliotas
• 金额: $ 126.01万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW019795%2F1
• 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.

为了从分子的细节上理解生物过程，人们需要捕捉和可视化蛋白质的作用。现代结构生物学方法，如x射线晶体学和低温电子显微镜（CryoEM）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。利兹最新的最先进的电子顺磁共振（EPR）光谱仪将能够提取蛋白质位点上未配对电子对之间的精确距离，从而充当分子纳米尺度的标尺。精确测量蛋白质功能周期的距离，将有助于阐明基本的生物过程。脉冲EPR是现代生物分子研究中的一种强有力的方法，在过去的10年里，它取得了巨大的技术进步，灵敏度提高了一个多数量级。作为利兹的蛋白质结构分子生物学家网络（包括几位领先的EPR专家），认为PELDOR是未来生物科学的关键途径。我们在利兹、全国（帝国理工学院、国王学院、格拉斯哥大学、圣安德鲁斯大学）和国外（欧盟、澳大利亚和印度）拥有非常庞大的用户基础，并且拥有无与伦比的各种基本生物系统，包括所有生命领域的代表性蛋白质。这些蛋白参与广泛的疾病相关生物学机制，从癌症和神经退行性疾病到抗微生物药物耐药性和代谢。新的EPR光谱仪将首次揭示目前无法通过其他方法获得的分子细节基础生物机制的新信息。我们的研究人员，合作者和行业合作伙伴来自广泛的国家和国际机构。我们在EPR、生物和医学科学领域有着广泛的业绩记录，预计此次安装将大大提高英国在全球生物EPR领域的能力和声誉。我们的商业案例将确保利兹中心的可持续性，并将服务于东北和其他大学，正如我们积极支持生物帝国的团体和调查人员所展示的那样。通过利兹大学的捐款，EPR工作人员科学家的职位将在最初的两年里得到保证。此外，将对预定的地点进行全面整修，并将购买一台冷却器，以使光谱仪能够最佳地安装和操作。该仪器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。这些升级将使英国保持国际竞争力，并继续发展和应用EPR方法解决生物科学领域的重要问题。

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