Mechanism-based development of small molecule probes for functional studies of bacterial E3 ubiquitin ligases

细胞内的通信——一个被称为细胞信号传导的过程——必须受到严格的调节，以确保细胞对任何内部或外部变化做出适当的反应。例如，当一个细胞被细菌或病毒感染时，它应该产生分子，提醒周围的细胞注意危险，并引发免疫反应。如果这种交流中断或信号过度活跃，就会产生毁灭性的影响，导致许多类型的疾病。蛋白质是大分子，在我们的身体中起着至关重要的作用。例如，它们锻炼肌肉，进行化学反应（酶）或充当信使（某些激素）。控制细胞信号传导的一种常用方法是用小分子（化学“标签”）修饰蛋白质，从而改变它们在细胞内的行为或位置。一种这样的修饰剂是小蛋白泛素，它可以附着在其他蛋白质上，这个过程被称为泛素化。蛋白质泛素化调节许多细胞过程，包括免疫反应和DNA损伤修复。泛素化系统的缺陷与许多疾病有关，包括癌症、自身免疫性疾病和神经退行性疾病。细菌不含泛素系统。然而，一些致病细菌已经进化出一种蛋白质，这种蛋白质能够劫持人体泛素系统，破坏对抵抗感染很重要的宿主蛋白质。在这个项目中，我们将研究这些细菌蛋白质是如何工作的。我们将利用这些新知识来生产能够特异性抑制这些细菌蛋白质作用的小化学分子，并帮助我们更好地了解它们是如何劫持人类泛素系统的。这项研究可能会提出治疗细菌感染的新方法，这是迫切需要的，以应对对抗生素治疗产生耐药性的细菌的增加。

Communication within a cell - a process called cell signalling - has to be very tightly regulated to ensure that the cell responds appropriately to any internal or external changes. For example, when a cell is infected with bacteria or viruses, it should produce molecules that alert surrounding cells to the danger and provoke an immune response. If this communication breaks down or the signals are overactive then this can have devastating effects, causing many types of disease.Proteins are macromolecules that play essential roles in our body. For example, they build muscles, carry out chemical reactions (enzymes) or act as messengers (some hormones). A common way of controlling cell signalling is the modification of proteins with small molecules (chemical 'tags'), which change their behaviour or location within a cell. One such modifier is the small protein ubiquitin that can be attached to other proteins - a process called ubiquitination. Protein ubiquitination regulates many cellular processes including immune responses and DNA damage repair. Defects in the ubiquitination system have been linked to many diseases including cancer, autoimmune and neurodegenerative disorders.Bacteria do not contain a ubiquitin system. However, some disease-causing bacteria have evolved to produce a type of protein that is able to hijack the human ubiquitin system to destroy host proteins that are important to fight infection. In this project we will study how these bacterial proteins work. We will use this new knowledge to produce small chemical molecules that can specifically inhibit the action of these bacterial proteins and help us to better understand how they hijack the human ubiquitin system. This research may suggest novel ways to treat bacterial infections, something that is urgently needed to deal with the rise of bacteria that are resistant to treatment with antibiotics.