Crystal structure of Schistosoma mansoni cathepsin D1 in complex with a nanobody reveals the conformation of the propeptide-bound stateKelly L. Parker, John D. Clarke, Xiaojiao Liu, Barbara F. Gomes, Lauren E.-A. Eyssen, Nicholas Furnham, Floriano Paes Silva-Jr, Raymond J. Owens [1] Molecular Tour Schistomiasis, also known as Bilhazia, is a tropical disease caused by parasitic worms and transmitted by freshwater snails. In a complex life cycle that involves a blood borne stage, the Schistosome worm produces proteases that digest haemaglobin, providing the amino acids that are essential for survival of the parasite. One of these digestive enzymes found in the gut of the parasite is the aspartyl protease, CathepsinD1 and given its key role in the life cycle of the schistosome worms is a potential drug target for treating Schistomiasis. Like other aspartyl proteases, Schistosome Cathepsin D1 is produced as an inactive pro-enzyme or zymogen so that it can be stored by the worm and only becomes catalytically active on exposure to the acidic pH in the gut of the parasite. Activation involves cleavage of a specific peptide sequence at the amino terminus of the enzyme which in turn exposes the active site. A lysine residue from this region forms salt-bridge interactions with the catalytic aspartates, providing a structural explanation for maintenance of the inactive state. We have determined the first crystal structure of Cathepsin D1 zymogen from the parasite, Schistosoma mansoni (abbreviated as SmCD1) revealing the conformation of the inactive enzyme. By immunising a llama with purified SmCD1, we produced a single-domain antibody (nanobody) that bound with high affinity to the enzyme and determined the structure of the enzyme in complex with the nanobody. Comparison of SmCD1 to human Cathepsin D (hCD) and human Cathepsin E (hCE) shows that their structures are largely conserved, with the active-site residues positioned in equivalent locations. Despite this structural similarity, the anti-SmCD1 nanobody did not bind to the human homologues, recognising a sequence that is conserved in schistosome parasites but not the human enzymes. Therefore, the nanobody provides a schistosome-specific tool and identifies a binding epitope on the enzyme for future structure-guided drug design of novel therapeutics for schistosomiasis.
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