Structural biology of soft tick complement inhibitor (OMCI) alone and in complex with C5

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The complement system is a group of approx. 30 proteins that act together to form a frontline defence against invasion by parasites and other pathogens. As for all proteins we can only really understand the ways in which these proteins act to combat invasion by knowledge of their detailed, atomic, structure. However, many of the complement system proteins are difficult to study at this level of detail and we therefore have little atomic level structural information for the central components of this important biological system. Most parasites attempt to overcome the defence mounted by the complement system by expressing molecules that act specifically to interfere with these defences. This application seeks to use an anti-complement molecule expressed by a tick to increase our understanding both of how the tick protein works (by solving the atomic structure of this inhibitor) and also to increase our understanding of one of the key complement components, a protein called C5, by discovering precisely how the tick inhibitors prevent its correct functioning. A vital first step towards this aim is the identification of the site of interaction between C5 and the inhibitor. We will use a variety of different biochemical methods to identify the site of interaction. Including (1) determining which fragments of C5 bind to the inhibitor, (2) studying the interaction between C5 and inhibitor in competition with complement components which bind to C5, and (3) introducing single amino acid changes to C5 that prevent the inhibitor binding. Armed with these data and materials (purified fragments of C5) we will attempt to determine an atomic structure for a complex between C5 (or a significant part of it) and the tick inhibitor to give us a framework on which to interpret our biochemical data and prior knowledge of the biological function of C5.