Cathepsin D-type aspartic proteases are importantly involved in acidic proteolysis in vertebrates and invertebrates. They are biosynthesized as inactive zymogens in which the propeptide sterically blocks the active site. We investigated the mechanism of the propeptide interaction in IrCD1, a hemoglobinolytic cathepsin D of the hard tick Ixodes ricinus. First, we determined crystal structures of the IrCD1 zymogen and the mature enzyme generated by autocatalytic removal of the propeptide. An exosite was identified in the enzyme core that plays a critical role in binding the propeptide. Second, we showed that the synthetic exosite-binding segment of the propeptide is an effective inhibitor of the mature IrCD1. Its interaction associated with induced conformational changes was demonstrated by the crystal structure of the complex. The study provides the first structure of cathepsin D zymogen and defines the propeptide-binding exosite as a target for the development of specific cathepsin D inhibitors.