Structures of proteinase-inhibitor complexes

Quite a number of serine proteinases have been implicated in cancer progression, and many of these are potential targets for drug therapy. For many proteinases, naturally occurring protein inhibitors provide leads for highly potent and selective inhibitors of potential therapeutic use. However, some serine proteinases have no known endogenous inhibitors, or are resistant to inhibition by protein inhibitors. Developing the means for therapeutic inhibition of such proteinases requires biochemical and structural studies elucidating the details of the enzyme active sites and their interactions with potential inhibitors. We are using biochemical techniques and protein crystallography to investigate the interactions of proteinase-inhibitor and proteinase-substrate complexes, to enable rational structure-based drug design.