Grant: Operating Grant

Pathogenic bacteria cause infection and illness in many ways, including injecting bacterial proteins into human cells so that our cells do not work properly. The proteins that these bacteria inject make people sick by interfering with the normal functioning of human cells. To combat these pathogens, we need to understand how these bacterial proteins bind to human proteins and interfere with normal cell functions. Structural biology allows us to 'see' the microscopic details of how proteins interact. If we can understand this process at the level of molecules, we can develop novel therapies for treating bacterial infections. As part of our proposed research, we have cataloged a list of secreted bacterial proteins, called effectors, from three disease-causing bacteria, Salmonella, Legionella and E. coli, and made a list of which proteins they interact with in human cells. As many of the bacterial proteins do not have a known binding partner, we will use specific experiments to identify the corresponding human protein(s) that interact with the bacterial proteins. These experiments will be performed both in cells (in vivo) and without cells (in vitro). Together these experiments will tell us which combinations of proteins interact with one another so that we can focus protein structural studies on these pairs of proteins. Various methods of structural biology (X-ray crystallography, nuclear magnetic resonance spectroscopy, small-angle X-ray scattering and electron microscopy) will be employed to see how these protein molecules interact. Together, the results of these experiments will provide details on how bacterial and human proteins bind to each other and help in the design of novel treatments to fight bacterial infections.