4I04

Structure of zymogen of cathepsin B1 from Schistosoma mansoni

Summary for 4I04

• Entry DOI: 10.2210/pdb4i04/pdb
• Related: 3QSD 3S3Q 3S3R 4I05 4I07
• Descriptor: Cathepsin B-like peptidase (C01 family), 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: peptidase, digestive tract, hydrolase
• Biological source: Schistosoma mansoni (Blood fluke)
• Total number of polymer chains: 4
• Total formula weight: 147285.24

Authors

Rezacova, P.,Jilkova, A.,Brynda, J.,Horn, M.,Mares, M. (deposition date: 2012-11-16, release date: 2014-02-05, Last modification date: 2024-11-13)

Primary citation

Jilkova, A.,Horn, M.,Rezacova, P.,Maresova, L.,Fajtova, P.,Brynda, J.,Vondrasek, J.,McKerrow, J.H.,Caffrey, C.R.,Mares, M.
Activation route of the Schistosoma mansoni cathepsin B1 drug target: structural map with a glycosaminoglycan switch
Structure, 22:1786-1798, 2014

PubMed Abstract: Cathepsin B1 (SmCB1) is a digestive protease of the parasitic blood fluke Schistosoma mansoni and a drug target for the treatment of schistosomiasis, a disease that afflicts over 200 million people. SmCB1 is synthesized as an inactive zymogen in which the N-terminal propeptide blocks the active site. We investigated the activation of the zymogen by which the propeptide is proteolytically removed and its regulation by sulfated polysaccharides (SPs). We determined crystal structures of three molecular forms of SmCB1 along the activation pathway: the zymogen, an activation intermediate with a partially cleaved propeptide, and the mature enzyme. We demonstrate that SPs are essential for the autocatalytic activation of SmCB1, as they interact with a specific heparin-binding domain in the propeptide. An alternative activation route is mediated by an S. mansoni asparaginyl endopeptidase (legumain) which is downregulated by SPs, indicating that SPs act as a molecular switch between both activation mechanisms.

PubMed: 25456815
DOI: 10.1016/j.str.2014.09.015

Experimental method

X-RAY DIFFRACTION (1.95 Å)