6BU7
Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor RD130 1-[2-(Piperidin-4-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole
Summary for 6BU7
| Entry DOI | 10.2210/pdb6bu7/pdb |
| Related | 4NEV 6BTL |
| Descriptor | Trypanothione reductase, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | trypanosoma, inhibitor, complex, sleeping sickness, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Trypanosoma brucei brucei (strain 927/4 GUTat10.1) |
| Total number of polymer chains | 2 |
| Total formula weight | 110817.73 |
| Authors | Bryson, S.,De Gasparo, R.,Krauth-Siegel, R.L.,Diederich, F.,Pai, E.F. (deposition date: 2017-12-08, release date: 2018-06-06, Last modification date: 2024-11-06) |
| Primary citation | De Gasparo, R.,Brodbeck-Persch, E.,Bryson, S.,Hentzen, N.B.,Kaiser, M.,Pai, E.F.,Krauth-Siegel, R.L.,Diederich, F. Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma. ChemMedChem, 13:957-967, 2018 Cited by PubMed Abstract: The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (K ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half-maximal inhibitory concentration, IC ) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X-ray co-crystal structures confirmed the binding of the ligands to the hydrophobic wall of the "mepacrine binding site" with the new, solubility-providing vectors oriented toward the surface of the large active site. PubMed: 29624890DOI: 10.1002/cmdc.201800067 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.73 Å) |
Structure validation
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