5ogq

Structure of cathepsin B1 from Schistosoma mansoni in complex with WRR391 inhibitor

spinqualitylabelsall models 5ogq, resolution 1.91Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ogq is a 3 chain structure with sequence from Schistosoma mansoni. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.91Å Ligands: 9U8, ACT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8MNY2_SCHMA Publication Abstract from PubMed Schistosomiasis, a parasitic disease caused by blood flukes of the genus Schistosoma, is a global health problem with over 200 million people infected. Treatment relies on just one drug, and new chemotherapies are needed. Schistosoma mansoni cathepsin B1 (SmCB1) is a critical peptidase for the digestion of host blood proteins and a validated drug target. We screened a library of peptidomimetic vinyl sulfones against SmCB1 and identified the most potent SmCB1 inhibitors reported to date that are active in the subnanomolar range with second order rate constants (k2nd) of approximately 2 x 10(5) M(-1) s(-1). High resolution crystal structures of the two best inhibitors in complex with SmCB1 were determined. Quantum chemical calculations of their respective binding modes identified critical hot spot interactions in the S1' and S2 subsites. The most potent inhibitor targets the S1' subsite with an N-hydroxysulfonic amide moiety and displays favorable functional properties, including bioactivity against the pathogen, selectivity for SmCB1 over human cathepsin B, and reasonable metabolic stability. Our results provide structural insights for the rational design of next-generation SmCB1 inhibitors as potential drugs to treat schistosomiasis. Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors.,Jilkova A, Rubesova P, Fanfrlik J, Fajtova P, Rezacova P, Brynda J, Lepsik M, Mertlikova-Kaiserova H, Emal CD, Renslo AR, Roush WR, Horn M, Caffrey CR, Mares M ACS Infect Dis. 2020 Nov 11. doi: 10.1021/acsinfecdis.0c00501. PMID:33175511 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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