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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

基本信息

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

项目摘要

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光谱（NMR）的技术来研究形成细胞和有机体复杂机制的生物分子的结构。它们的结构决定了它们如何工作和相互作用，并形成了人类在理解尖端生物科学方面所做的大量努力的基础。我们建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，设计新生物分子的结构或生产抗病毒，抗生素和抗真菌化合物等领域取得突破性发现。我们还可以使用这些新的核磁共振数据来设计或重新利用药物，使它们更有效，甚至可以看看当您的身体试图代谢下一代药物时，它们会发生什么。我们已经确定了超过3000万英镑的资助研究计划，国家合作和博士培训计划，该仪器将从第一天起提供支持，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仪器的使用寿命内大幅增加这一点。新的探针将使这项研究成为可能，因为NMR与医院中的全身MRI扫描仪具有相同的基本思想。然而，当研究生物科学中的分子时，很难获得足够的样品来用我们的NMR光谱仪检测，并且MRI研究的“标准”原子核（质子）往往非常丰富，以至于它给出了非常“嘈杂”的光谱，其中有太多的信号，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”，该探针具有非常灵敏的检测能力，并且经过优化可以观察其他类型的原子核，这些原子核往往会给出更多分散的信号。一些核磁共振系统已经开始使用碳和氮原子核，但是我们将要安装的这个TXO-HF系统特别强大的原因是它还可以使用另一个原子核，氟，作为探针是非常强大的，因为它在大多数自然系统中是罕见的。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，然后在没有质子NMR发现的所有背景噪音的情况下跟踪它的行为，从而研究生物学中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，我们与许多合作伙伴大学，国家NMR网络计划和生物制药公司合作。通过将所有这些不同的团体聚集在一起，我们确保我们最大限度地增加了人员数量，并拥有广泛的专业知识，可以应用于我们面临的科学挑战。随着全国大学合作情况的演变，分享（昂贵！）像这样独特而精密的设备变得越来越重要。因此，我们正在寻求用这种设备做的一部分是用它作为一个范例，以鼓励合作和培训我们熟练的研究技术专业人员谁运行这些仪器，以及激励学生谁自己将继续成为未来的生物科学研究人员和核磁共振波谱仪。为此，我们与一个专门的团队合作，他们支持这一想法，我们希望通过他们使设备更具影响力和可持续性。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

DOI：
10.1002/anie.202212393
发表时间：
2022-12-12
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
影响因子：
16.6
作者：
Winter, Ashley J.;Rowe, Matthew T.;Weir, Angus N. M.;Akter, Nahida;Mbatha, Sbusisiwe Z.;Walker, Paul D.;Williams, Christopher;Song, Zhongshu;Race, Paul R.;Willis, Christine L.;Crump, Matthew P.
通讯作者：
Crump, Matthew P.

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