3IUT
The Crystal Structure of Cruzain in Complex with a Tetrafluorophenoxymethyl Ketone Inhibitor
Summary for 3IUT
| Entry DOI | 10.2210/pdb3iut/pdb |
| Descriptor | Cruzipain, (3S)-3-(4-{(1S)-1,2-dimethyl-1-[(quinolin-6-ylmethyl)amino]propyl}-1H-1,2,3-triazol-1-yl)heptan-2-one, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | mature domain, papain family cysteine protease, autocatalytic cleavage, disulfide bond, glycoprotein, hydrolase, protease, thiol protease, zymogen |
| Biological source | Trypanosoma cruzi |
| Total number of polymer chains | 1 |
| Total formula weight | 24153.81 |
| Authors | Kerr, I.D.,Debnath, M.,Brinen, L.S. (deposition date: 2009-08-31, release date: 2010-03-02, Last modification date: 2024-11-06) |
| Primary citation | Brak, K.,Kerr, I.D.,Barrett, K.T.,Fuchi, N.,Debnath, M.,Ang, K.,Engel, J.C.,McKerrow, J.H.,Doyle, P.S.,Brinen, L.S.,Ellman, J.A. Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for chagas disease chemotherapy. J.Med.Chem., 53:1763-1773, 2010 Cited by PubMed Abstract: 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. PubMed: 20088534DOI: 10.1021/jm901633v PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.2 Å) |
Structure validation
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