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Elucidating and exploiting docking domain-mediated carrier protein recognition in natural product megasynthetases

阐明和利用天然产物大合成酶中对接域介导的载体蛋白识别

基本信息

批准号：
BB/R010218/1
负责人：
Józef Lewandowski
金额：
$ 94.55万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR010218%2F1
关键词：
Elucidating exploiting docking domain mediated

项目摘要

Bioactive natural products from plants and microorganisms have numerous important applications in medicine and agriculture. They are used to tackle life-threating conditions, such as bacterial and fungal infections, organ transplant rejection and cancer, and as herbicides, insecticides and fungicides that play an essential role in the protection of food crops. Many natural products are assembled by enzymatic "assembly lines", akin to a car production line. Each component of the assembly line must engage in effective communication with the next to ensure the overall process is efficient. Such communication is typically mediated by dedicated "docking domains" attached to the ends of the components, which interact with each other in a specific way. We have been studying the role played by a particular type of docking domain and its interaction partner in the assembly of enacyloxin IIa. This antibiotic is produced by Burkholderia species and has potent activity against Acinetobacter baumannii, a bacterium that causes life threatening diseases in humans for which there is a critical need to find effective new treatments. Our data have shown that this type of docking domain is involved in the assembly of many more bioactive natural products than previously thought, including several anti-cancer agents and an antibiotic that are used in the clinic. In this project we aim to use a combination of established and recently-developed techniques to develop a better understanding of the way the docking domain involved in the production of enacyloxin recognises its interaction partner. The insights we obtain will be used to modify the enacyloxin assembly line to see whether it behaves in the way we predict. We also aim to investigate a related system in which two components, both of which have a docking domain that is similar to the one involved in enacyloxin production, appear to interact with the same partner to execute sequential tasks in the assembly of the aeruginosins, an unusual group of protein degradation inhibitors produced by cyanobacteria. This will broaden our understanding of the role played by docking domains in natural product assembly and allow us to establish the common principles underlying the way in which they recognise their interaction partners. Finally, we will investigate whether our understanding of these common principles can be harnessed to substitute one of the components of the aeruginosin assembly line with the corresponding component from the enacyloxin system. Overall, this project will significantly deepen our understanding of the roles played by an important type of docking domain in natural product assembly and will establish the feasibility of exploiting such docking domains to construct engineered assembly lines capable of producing novel natural product hybrids.

来自植物和微生物的生物活性天然产物在医药和农业中有许多重要的应用。它们被用来应对威胁生命的疾病，如细菌和真菌感染、器官移植排斥反应和癌症，以及在保护粮食作物方面发挥关键作用的除草剂、杀虫剂和杀菌剂。许多天然产品都是由酶类“流水线”组装而成，类似于汽车生产线。装配线上的每个部件都必须与下一个部件进行有效的沟通，以确保整个流程的高效。这种通信通常由连接到组件末端的专用“停靠域”进行中介，这些停靠域以特定的方式彼此交互。我们一直在研究一种特定类型的对接结构域及其相互作用伙伴在组装纳西洛辛IIa中所起的作用。这种抗生素是由伯克霍尔德氏菌产生的，对鲍曼不动杆菌有很强的活性，鲍曼不动杆菌是一种导致人类危及生命的疾病的细菌，迫切需要找到有效的新治疗方法。我们的数据表明，这种类型的对接结构域参与了许多比之前认为的更具生物活性的天然产物的组装，包括几种抗癌药物和一种临床使用的抗生素。在这个项目中，我们的目标是使用现有的和最近开发的技术相结合的方法来更好地理解生产阿曲洛辛的对接领域识别其交互伙伴的方式。我们获得的见解将被用来修改阿昔洛辛装配线，看看它的行为是否符合我们的预测。我们还旨在研究一个相关系统，在该系统中，两个组件的对接结构域都类似于生产阿曲洛辛的组件，它们似乎与同一个合作伙伴相互作用，执行铜绿球蛋白组装中的连续任务。铜绿球蛋白是蓝藻产生的一组不寻常的蛋白质降解抑制剂。这将扩大我们对对接域在天然产品组装中所起作用的理解，并使我们能够建立它们识别其交互伙伴的方式所依据的共同原则。最后，我们将调查是否可以利用我们对这些共同原则的理解，将铜绿球蛋白装配线上的一个部件替换为来自阿昔洛辛系统的相应部件。总体而言，该项目将显著加深我们对一种重要的对接结构域在天然产品组装中所起作用的理解，并将建立利用这种对接结构域构建能够生产新型天然产品杂交产品的工程装配线的可行性。