4NEV

Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor EP127 (5-{5-[1-(PYRROLIDIN-1-YL)CYCLOHEXYL]-1,3-THIAZOL-2-YL}-1H-INDOLE)

Summary for 4NEV

• Entry DOI: 10.2210/pdb4nev/pdb
• Descriptor: Trypanothione reductase, FLAVIN-ADENINE DINUCLEOTIDE, 5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole, ... (6 entities in total)
• Functional Keywords: reductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 2
• Total formula weight: 110628.37

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: 2024-11-27)

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

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: 24788386
DOI: 10.1002/cmdc.201402032

Experimental method

X-RAY DIFFRACTION (2.5 Å)