3lxs | pdb_00003lxs

Crystal structure analysis of cruzain bound to vinyl sulfone derived inhibitor (WRR483)

spinqualitylabelsall models 3lxs, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3lxs is a 2 chain structure with sequence from Trypanosoma cruzi. This structure supersedes the now removed PDB entry 2efm. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.5Å Ligands: 4MC, EDO, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CYSP_TRYCR Hydrolyzes chromogenic peptides at the carboxyl Arg or Lys; requires at least one more amino acid, preferably Arg, Phe, Val or Leu, between the terminal Arg or Lys and the amino-blocking group. The cysteine protease may play an important role in the development and differentiation of the parasites at several stages of their life cycle. Publication Abstract from PubMed BACKGROUND: Cruzain, the major cysteine protease of Trypanosoma cruzi, is an essential enzyme for the parasite life cycle and has been validated as a viable target to treat Chagas' disease. As a proof-of-concept, K11777, a potent inhibitor of cruzain, was found to effectively eliminate T. cruzi infection and is currently a clinical candidate for treatment of Chagas' disease. METHODOLOGY/PRINCIPAL FINDINGS: WRR-483, an analog of K11777, was synthesized and evaluated as an inhibitor of cruzain and against T. cruzi proliferation in cell culture. This compound demonstrates good potency against cruzain with sensitivity to pH conditions and high efficacy in the cell culture assay. Furthermore, WRR-483 also eradicates parasite infection in a mouse model of acute Chagas' disease. To determine the atomic-level details of the inhibitor interacting with cruzain, a 1.5 A crystal structure of the protease in complex with WRR-483 was solved. The structure illustrates that WRR-483 binds covalently to the active site cysteine of the protease in a similar manner as other vinyl sulfone-based inhibitors. Details of the critical interactions within the specificity binding pocket are also reported. CONCLUSIONS: We demonstrate that WRR-483 is an effective cysteine protease inhibitor with trypanocidal activity in cell culture and animal model with comparable efficacy to K11777. Crystallographic evidence confirms that the mode of action is by targeting the active site of cruzain. Taken together, these results suggest that WRR-483 has potential to be developed as a treatment for Chagas' disease. In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.,Chen YT, Brinen LS, Kerr ID, Hansell E, Doyle PS, McKerrow JH, Roush WR PLoS Negl Trop Dis. 2010 Sep 14;4(9). pii: e825. PMID:20856868 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cruzain

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