Crystal structure of Schistosoma mansoni cathepsin D1 in complex with a nanobody reveals the conformation of the propeptide-bound state

Schistosoma mansoni cathepsin D1 ( Sm CD1) has been shown to be an essential enzyme for helminth metabolism due to its role in haemoglobin degradation: a key amino-acid source for the developing parasite. Therefore, the enzyme is a potential target for the development of antischistosomal inhibitors. Sm CD1 has significant sequence identity to cathepsin D-like proteases found in other schistosome species and homology to mammalian aspartic proteases. Here, we report the first crystal structures of a helminth cathepsin D, Sm CD1, and have identified a single-domain antibody (nanobody) that specifically binds to Sm CD1 with nanomolar affinity but does not recognize human cathepsin D. We have mapped the epitope of the nanobody by determining the crystal structure of the enzyme–nanobody complex, revealing the conformation of Sm CD1 in the propeptide-bound state.