3S3R

Structure of cathepsin B1 from Schistosoma mansoni in complex with K11777 inhibitor

Summary for 3S3R

• Entry DOI: 10.2210/pdb3s3r/pdb
• Related: 3QSD 3S3Q
• Related PRD ID: PRD_000325
• Descriptor: Cathepsin B-like peptidase (C01 family), Nalpha-[(4-methylpiperazin-1-yl)carbonyl]-N-[(3S)-1-phenyl-5-(phenylsulfonyl)pentan-3-yl]-L-phenylalaninamide (3 entities in total)
• Functional Keywords: peptidase, digestive tract, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Schistosoma mansoni (Blood fluke)
• Total number of polymer chains: 3
• Total formula weight: 87252.02

Authors

Rezacova, P.,Jilkova, A.,Brynda, J.,Horn, M.,Mares, M. (deposition date: 2011-05-18, release date: 2011-08-10, Last modification date: 2024-10-30)

Primary citation

Jilkova, A.,Rezacova, P.,Lepsik, M.,Horn, M.,Vachova, J.,Fanfrlik, J.,Brynda, J.,McKerrow, J.H.,Caffrey, C.R.,Mares, M.
Structural Basis for Inhibition of Cathepsin B Drug Target from the Human Blood Fluke, Schistosoma mansoni.
J.Biol.Chem., 286:35770-35781, 2011

PubMed Abstract: Schistosomiasis caused by a parasitic blood fluke of the genus Schistosoma afflicts over 200 million people worldwide. Schistosoma mansoni cathepsin B1 (SmCB1) is a gut-associated peptidase that digests host blood proteins as a source of nutrients. It is under investigation as a drug target. To further this goal, we report three crystal structures of SmCB1 complexed with peptidomimetic inhibitors as follows: the epoxide CA074 at 1.3 Å resolution and the vinyl sulfones K11017 and K11777 at 1.8 and 2.5 Å resolutions, respectively. Interactions of the inhibitors with the subsites of the active-site cleft were evaluated by quantum chemical calculations. These data and inhibition profiling with a panel of vinyl sulfone derivatives identify key binding interactions and provide insight into the specificity of SmCB1 inhibition. Furthermore, hydrolysis profiling of SmCB1 using synthetic peptides and the natural substrate hemoglobin revealed that carboxydipeptidase activity predominates over endopeptidolysis, thereby demonstrating the contribution of the occluding loop that restricts access to the active-site cleft. Critically, the severity of phenotypes induced in the parasite by vinyl sulfone inhibitors correlated with enzyme inhibition, providing support that SmCB1 is a valuable drug target. The present structure and inhibitor interaction data provide a footing for the rational design of anti-schistosomal inhibitors.

PubMed: 21832058
DOI: 10.1074/jbc.M111.271304

Experimental method

X-RAY DIFFRACTION (2.64 Å)