Bacterial modification of carbohydrates; structural and functional analysis of a key virulence strategy.

许多细菌病原体都有一个共同的增强毒力和持久性的机制；它们产生的酶可以修改细菌细胞表面的碳水化合物。这种修饰可以帮助逃避免疫系统(例如，修改沙门氏菌中的O-抗原)，促进生物膜的形成(金黄色葡萄球菌)或提供对渗透胁迫的保护(大肠杆菌)；抑制这些酶可能会产生新的抗生素。为了开发这些蛋白质作为潜在的新的治疗靶点，关于结构和功能之间的关系有许多问题需要回答。这项应用的目的是研究这个蛋白质家族的成员OpgC，它能使革兰氏阴性细菌病原体中的周质葡聚糖琥珀酸化。该项目将在结构生物学、生物物理学和分子微生物学方面采用跨学科的方法和尖端技术。像许多目前的药物靶点一样，OpgC是一种完整的膜蛋白，因此该项目也将在处理这些具有挑战性的蛋白质的技术方面提供宝贵的经验。您将接受重组蛋白方面的培训，包括膜蛋白、表达和纯化、使用新型酰基供体模拟物开发膜蛋白功能分析以及生物物理/结构表征，包括适当的核磁共振波谱和X射线结晶学。生物系的技术设施还包括各种设施，包括用于表征修饰底物的最先进的质谱仪。实验室会议、系列研讨会、小型研讨会以及参与和发展外展活动的机会将帮助您培养广泛的科学技能和可移植技能。有一个充满活力的博士社区，举办像咖啡和职业这样的活动。你将被共同监督，并在生物化学、结构生物学和微生物学专业的实验室进行这项工作。这个项目适合对生物化学有很强的背景和兴趣，并对细菌致病的分子基础总体感兴趣的申请者。

Many bacterial pathogens share a common mechanism for enhancing virulence and persistence; they produce enzymes that modify carbohydrates on the bacterial cell surface. The modification may aid evasion of the immune system (for example modification of the O-antigen in Salmonella sp.), enhance biofilm formation (Staphylococcus aureus) or provide protection from osmotic stress (Escherichia coli); inhibiting these enzymes could lead to new antibiotics. With a view to developing these proteins as potential new therapeutic targets, there are many questions that need to be answered regarding the relationship between structure and function. The aim of this application is to investigate a member of this protein family, OpgC, that succinylates periplasmic glucans in Gram-negative bacterial pathogens. The project will employ an interdisciplinary approach and cutting edge techniques in structural biology, biophysics and molecular microbiology. Like many current drug targets, OpgC is an integral membrane protein thus this project will also provide valuable experience in techniques for working with these challenging proteins. You will receive training in recombinant protein, including membrane protein, expression and purification, the development of functional assays for membrane proteins using novel acyl donor mimics and biophysical/structural characterisation including, as appropriate, NMR spectroscopy and X-ray crystallography. The Technology Facility in the Department of Biology also houses a wide range of facilities including state-of- the-art mass spectrometry for characterising modified substrates. Lab meetings, seminar series, minisymposia and the opportunity to participate in and develop outreach activities will help you develop a broad range of scientific and transferable skills. There is a vibrant PhD community that hosts events like Coffee and Careers. You will be co-supervised and will carry the work out in labs specializing in biochemistry, structural biology and microbiology. This project is suitable for applicants with a strong background and interest in biochemistry and an overall interest in the molecular basis of bacterial pathogenesis.