6OEZ
Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor (+)-N-(Cyclobutylmethyl)-3-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-2-(1-{[(2S)-pyrro-lidin-2-yl]methyl}-1H-indol-5-yl)-1,3-thiazol-4-yl}prop-2-yn-1-amine
Summary for 6OEZ
| Entry DOI | 10.2210/pdb6oez/pdb |
| Descriptor | Trypanothione reductase, FLAVIN-ADENINE DINUCLEOTIDE, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total) |
| Functional Keywords | trypanosoma, trypanothione, inhibitor, sleeping sickness, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Trypanosoma brucei brucei (strain 927/4 GUTat10.1) |
| Total number of polymer chains | 2 |
| Total formula weight | 110155.29 |
| Authors | Halgas, O.,De Gasparo, R.,Harangozo, D.,Krauth-Siegel, R.L.,Diederich, F.,Pai, E.F. (deposition date: 2019-03-28, release date: 2019-07-31, Last modification date: 2024-10-16) |
| Primary citation | De Gasparo, R.,Halgas, O.,Harangozo, D.,Kaiser, M.,Pai, E.F.,Krauth-Siegel, R.L.,Diederich, F. Targeting a Large Active Site: Structure-Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase. Chemistry, 25:11416-11421, 2019 Cited by PubMed Abstract: Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas' disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma (T.) brucei TR, with an inhibition constant K of 73 nm, which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC values (half-maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense, in the mid-nanomolar range, reaching down to 50 nm. X-Ray co-crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure-based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar K and IC values for in vivo studies. PubMed: 31407832DOI: 10.1002/chem.201901664 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
Download full validation report
