A globally unique 19F, 13C, 15N NMR system to enable frontier bioscience

全球独一无二的 19F、13C、15N NMR 系统，助力前沿生物科学

• 批准号: BB/V019163/1
• 负责人: Matthew Crump
• 金额: $ 87.9万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV019163%2F1
• 关键词: globally; unique; 19F; 13C; 15N

We use a technique called Nuclear Magnetic Resonance spectroscopy (NMR) to study the structure of biomolecules that form the intricate machinery of cells and organisms. Their structure determines how they work and interact with each other and forms the basis of considerable human effort in understanding cutting edge bioscience. We are proposing to purchase the world's first TXO-HF NMR cryogenic probe technology and use it to make ground-breaking discoveries in areas such as neurodegenerative conditions like Parkinson's disease, design the structure of new biomolecules, or the production of antiviral, antibiotic and antifungal compounds. We can also use this new NMR data to design or repurpose drugs to make them more potent and even look at what happens to next generation drugs when your body tries to metabolise them. We have already identified >£30m of funded research programs, national collaborations and doctoral training programs that this instrument will underpin from day one, and we are working with a range of national networks who will allow us to increase this substantially over the lifetime of the NMR instrument. The new probe will enable this research because NMR shares the same basic ideas as the whole-body MRI scanners that are found in hospitals. However when studying molecules in bioscience, it is difficult to get enough sample to detect with our NMR spectrometer and the 'standard' atomic nucleus that MRI studies (the proton), tends to be so abundant that it gives very 'noisy' spectra with too many signals for us to be able to interpret. The solution to these problems is to use an NMR 'cryoprobe' that has very sensitive detection and is optimised to look at other types of atomic nuclei that tend to give more spread-out signals. Some NMR systems have started to use carbon and nitrogen nuclei, but what makes this TXO-HF system we are going to install especially powerful is that it can also use a further nucleus, fluorine, that is uniquely powerful as a probe because it is rare in most natural systems. This means we can use cutting-edge biosynthetic techniques to introduce fluorine into the molecules we study and then follow it's behaviour without all of the background noise that is found with proton-based NMR and thus study some very difficult problems in biology. There are many more important and complex scientific questions to answer with this new equipment and to do this we have teamed up with many partner universities, national NMR network programs and biopharmaceutical companies. By bringing all of these different groups together we are ensuring we maximise the number of people and have a broad expertise that can be applied to the scientific challenges we face. As the national picture of how universities work together evolves, sharing (expensive!) unique and sophisticated equipment like this becomes ever more important. Therefore part of what we are seeking to do with this equipment is use it as an exemplar to encourage collaboration and training for our skilled research technical professionals who run these instruments, as well as to inspire the students who themselves will go on to be the bioscience researchers and NMR spectroscopists of the future. To do this we have engaged with a dedicated team who champion this idea and through which we hope to make the equipment even more impactful and sustainable.

我们使用一种称为核磁共振波谱 (NMR) 的技术来研究构成细胞和生物体的复杂机器的生物分子的结构。它们的结构决定了它们如何工作和相互作用，并构成了人类理解切割的大量努力的基础。我们提议购买世界上第一个 TXO-HF NMR 低温探针技术，并利用它在帕金森病等神经退行性疾病领域做出突破性发现，设计新的结构。我们还可以利用这些新的 NMR 数据来设计或重新利用药物，使其更有效，甚至可以观察下一代药物在您的身体尝试代谢时会发生什么情况。已经确定了超过 3000 万英镑的资助研究项目、国家合作和博士培训项目，该仪器从第一天起就将支持这些项目，我们正在与一系列国家网络合作，这些网络将使我们能够在 NMR 的生命周期内大幅增加这一项目乐器。新的探针将使这项研究成为可能，因为核磁共振与医院中使用的全身核磁共振扫描仪具有相同的基本原理。然而，在研究生物科学中的分子时，很难获得足够的样本来使用我们的核磁共振波谱仪和“核磁共振”进行检测。核磁共振研究的“标准”原子核（质子）往往非常丰富，以至于它会给出非常“嘈杂”的光谱，其中包含太多信号，我们无法解释这些问题的解决方案是使用核磁共振“冷冻探针”。那具有非常灵敏的检测能力，并经过优化，可检测其他类型的原子核，这些原子核往往会产生更多的扩散信号。一些 NMR 系统已开始使用碳核和氮核，但我们将安装这个 TXO-HF 系统。特别强大的是，它还可以使用另一个核，氟，作为探针具有独特的强大功能，因为它在大多数自然系统中很少见，这意味着我们可以使用尖端的生物合成技术将氟引入我们研究的分子中，然后。跟随它的行为没有基于质子的核磁共振发现的所有背景噪音，因此可以研究生物学中的一些非常困难的问题。有许多更重要和复杂的科学问题需要用这种新设备来回答，为了做到这一点，我们已经合作了。许多合作大学、国家核磁共振网络项目和生物制药公司将所有这些不同的团体聚集在一起，我们确保最大限度地增加人员数量，并拥有可应用于我们面临的科学挑战的广泛专业知识。大学如何共同发展，共享（昂贵！）像这样独特而复杂的设备变得越来越重要，因此我们寻求使用该设备的部分目的是将其作为范例来鼓励运行这些仪器的熟练研究技术专业人员的合作和培训，并激励学生成为未来的生物科学研究人员和核磁共振波谱学家。为此，我们与支持这一想法的专业团队合作，我们希望通过该团队使设备更具影响力。和可持续的。

项目成果

An N-terminal alpha-synuclein fragment binds lipid vesicles to modulate lipid-induced aggregation

N 末端 α-突触核蛋白片段结合脂质囊泡以调节脂质诱导的聚集

• DOI: http://dx.10.1016/j.xcrp.2023.101563
• 发表时间: 2023
• 期刊: Cell Reports Physical Science
• 影响因子: 8.9
• 作者: Meade R

Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin.

程序化迭代控制抗生素莫匹罗星壬酸侧链的组装。

• DOI: http://dx.10.1002/anie.202212393
• 发表时间: 2022
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Winter AJ

X-ray structure of the metastable SEPT14-SEPT7 coiled coil reveals a hendecad region crucial for heterodimerization

亚稳态SEPT14-SEPT7卷曲线圈的X射线结构揭示了对异二聚化至关重要的十六进制区域

• DOI: http://dx.10.1107/s2059798323006514
• 发表时间: 2023
• 期刊: Acta Crystallographica Section D Structural Biology
• 作者: Cavini I

Structure and Function of the a-Hydroxylation Bimodule of the Mupirocin Polyketide Synthase

莫匹罗星聚酮合酶α-羟基化双模块的结构和功能

• DOI: http://dx.10.1002/anie.202312514
• 发表时间: 2023
• 期刊: Angewandte Chemie International Edition
• 作者: Winter A

The Role of Cytochrome P450 AbyV in the Final Stages of Abyssomicin C Biosynthesis.

细胞色素 P450 AbyV 在 Abyssomicin C 生物合成最后阶段的作用。

• DOI: http://dx.10.1002/anie.202213053
• 发表时间: 2023
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Devine AJ