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

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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.