3iut | pdb_00003iut

The Crystal Structure of Cruzain in Complex with a Tetrafluorophenoxymethyl Ketone Inhibitor

spinqualitylabelsall models 3iut, resolution 1.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3iut is a 1 chain structure with sequence from Trycr. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, KB2 Gene: cruzipain (TRYCR) Activity: Cruzipain, with EC number 3.4.22.51 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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogues in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy. Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for chagas disease chemotherapy.,Brak K, Kerr ID, Barrett KT, Fuchi N, Debnath M, Ang K, Engel JC, McKerrow JH, Doyle PS, Brinen LS, Ellman JA J Med Chem. 2010 Feb 25;53(4):1763-73. PMID:20088534 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cruzain

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