Centre for structural analysis of complex biological systems

复杂生物系统结构分析中心

• 批准号: BB/M012107/1
• 负责人: Ian Collinson
• 金额: $ 69.72万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM012107%2F1
• 关键词: Centre; structural; analysis; complex; biological

Understanding the function of the molecules of life requires knowledge of their three dimensional structures. Seeing, at or near to the level of individual atoms, how the building blocks of life (proteins and DNA) are assembled enables us to understand both how they may act to drive the chemical reactions that power and maintain living cells, and how they are organised into more complex structures that form the basis of cells and tissues. Detailed knowledge of structure can explain how specific alterations affect function, for example where changes to specific molecules are linked to disease, or how biological systems can be engineered to fulfil useful functions, such as making new drugs or turning carbon dioxide into liquid fuels.Most structures of biological molecules are derived from experiments where ordered crystals of the pure material are exposed to X-rays. The success of this approach relies upon inducing crystals to form. Unfortunately, for many interesting and important biological molecules this remains very difficult, and large numbers of experiments must be conducted to identify suitable conditions for crystal formation. However, recent technological developments have increased the number of experiments possible with limited amounts of material, and created automated systems to monitor the progress of experiments and detect crystals as they form. Furthermore, technology has improved our ability to create conditions mimicking those existing inside biological membranes (the structures that separate the cell interior from its surroundings and organise the cell into compartments) greatly simplifying the process of obtaining crystals of proteins that are normally associated with membranes. Such proteins perform key biological functions at the cell surface, enabling cells to recognise one another and to bind biological surfaces, and regulating the traffic of molecules, including other proteins, into and out of the cell. However, membrane proteins are much harder to work with, and hence less well understood, than other protein systems.Here we request funds to purchase equipment that will transform our ability to grow crystals, and obtain structures, of a range of biologically interesting but technically challenging targets. We will create a state-of-the-art Facility to exploit recent successes producing proteins and protein assemblies in the quantities necessary for crystallisation. Specifically, we wish to purchase: i) a robot to set up crystallisation experiments in conditions replicating the membrane environment; ii) an automated system to house the numbers of crystallisation experiments made possible by robotic systems working on small scales, and that will monitor their progress without human intervention; and iii) a complete crystallisation facility, including a robot to set up experiments and a microscope to inspect the results, maintained in a controlled, oxygen-free, environment. We will use this equipment to obtain structures of a number of biological molecules and assemblies including: the machinery controlling protein movement across membranes; the surface proteins of the human red blood cell that determine blood group, surface proteins from disease-causing bacteria that enable them to bind human cells; giant molecular machines synthesising drugs and antibiotics; the protein assembly by which cells carry out the instructions contained within genes; artificial proteins that carry electrons; and a wide range of proteins, involved in processes from bacterial antibiotic resistance to conversion of carbon dioxide into liquid fuels, that only function when oxygen is absent. Through our strong links to other local Universities our Facility, which will be unique within the region, will be open to researchers across the South West and South Wales, and will provide cutting edge instrumentation on which to provide the next generation of scientists with skills essential to the UK science and technology base.

了解生命分子的功能需要了解其三维结构。在单个原子的水平或附近，如何组装生命的构件（蛋白质和DNA），使我们能够了解它们如何采取行动来驱动能力和维持活细胞的化学反应，以及它们的方式组织成构成细胞和组织基础的更复杂的结构。详细的结构知识可以解释特定的变化如何影响功能，例如，在特定分子的变化与疾病相关的情况下，或如何设计生物系统以实现有用的功能，例如制造新药或将二氧化碳变成液体燃料。生物分子的结构源自实验，其中纯材料的有序晶体暴露于X射线。这种方法的成功依赖于诱导晶体形成。不幸的是，对于许多有趣且重要的生物分子，这仍然非常困难，并且必须进行大量实验以确定适当的晶体形成条件。但是，最近的技术发展增加了材料量有限的实验数量，并创建了自动化系统来监测实验的进展并检测晶体形成的过程。此外，技术提高了我们创造模仿那些内部生物膜的条件的能力（将细胞内部与周围环境区分开并将细胞组织成隔室的结构极大地简化了获得通常与膜相关的蛋白质晶体的过程。这种蛋白质在细胞表面执行关键的生物学功能，使细胞能够相互识别并结合生物表面，并调节包括其他蛋白质在内的分子的流量进入细胞。但是，与其他蛋白质系统相比，膜蛋白更难使用，因此理解得不太了解。具有挑战性的目标。我们将创建一个最先进的设施，以利用最新的成功，从而产生蛋白质和蛋白质组件的结晶量。具体来说，我们希望购买：i）在复制膜环境的条件下设置结晶实验的机器人； ii）一种自动化系统，用于容纳在小规模上工作的机器人系统使结晶实验的数量，这将在不干预的情况下监测其进度； iii）一个完整的结晶设施，包括设置实验的机器人和一个显微镜检查结果，并保持在受控的，无氧的环境中。我们将使用该设备获得许多生物分子和组件的结构，包括：控制跨膜蛋白质运动的机械；人类红细胞的表面蛋白决定血液群，从致病细菌中表面蛋白，使它们能够结合人类细胞；巨型分子机综合药物和抗生素；细胞在基因内包含指令的蛋白质组件；携带电子的人造蛋白质；从细菌抗生素耐药性到将二氧化碳转化为液体燃料的过程中，只有在不存在氧气时起作用。通过我们与其他当地大学的紧密联系，我们的设施将在该地区独一到英国科学技术基础。

项目成果

Resistance to the "last resort" antibiotic colistin: a single-zinc mechanism for phosphointermediate formation in MCR enzymes.

• DOI: 10.1039/d0cc02520h
• 发表时间: 2020-05
• 期刊: Chemical communications
• 影响因子: 4.9
• 作者: Emily Lythell;R. Suardíaz;P. Hinchliffe;Chonnikan Hanpaibool;Surawit Visitsatthawong;Sofia Oliveira;Eric J. M. Lang;Panida Surawatanawong;V. Lee;T. Rungrotmongkol;Natalie Fey;J. Spencer;A. Mulholland

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: 10.1002/ange.202213053
• 发表时间: 2022
• 期刊: Angewandte Chemie
• 作者: Devine A