4NEW
Crystal structure of Trypanothione Reductase from Trypanosoma cruzi in complex with inhibitor EP127 (5-{5-[1-(PYRROLIDIN-1-YL)CYCLOHEXYL]-1,3-THIAZOL-2-YL}-1H-INDOLE)
Summary for 4NEW
| Entry DOI | 10.2210/pdb4new/pdb |
| Related | 4NEV |
| Descriptor | Trypanothione reductase, putative, FLAVIN-ADENINE DINUCLEOTIDE, 5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole (3 entities in total) |
| Functional Keywords | reductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Trypanosoma cruzi |
| Total number of polymer chains | 1 |
| Total formula weight | 55072.76 |
| Authors | Persch, E.,Bryson, S.,Pai, E.F.,Krauth-Siegel, R.L.,Diederich, F. (deposition date: 2013-10-30, release date: 2014-05-14, Last modification date: 2024-10-16) |
| Primary citation | Persch, E.,Bryson, S.,Todoroff, N.K.,Eberle, C.,Thelemann, J.,Dirdjaja, N.,Kaiser, M.,Weber, M.,Derbani, H.,Brun, R.,Schneider, G.,Pai, E.F.,Krauth-Siegel, R.L.,Diederich, F. Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase. Chemmedchem, 9:1880-1891, 2014 Cited by PubMed Abstract: The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so-called "mepacrine binding site". The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi. PubMed: 24788386DOI: 10.1002/cmdc.201402032 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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