1. Inhibitor-Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes
- Author
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Hermann Schindelin, Thien Anh Le, Natalie Dirdjaja, Martha Brennich, Annika Wagner, Erika Diehl, D. Paszek, Bernd Engels, Ute A. Hellmich, A.K. Weickhmann, Philipp Klein, Till Opatz, Nicole Bader, and R.L. Krauth-Siegel
- Subjects
Trypanosoma ,Protein Conformation ,Spermidine ,Dimer ,Trypanosoma brucei brucei ,Antiprotozoal Agents ,Molecular Dynamics Simulation ,Trypanosoma brucei ,010402 general chemistry ,01 natural sciences ,Catalysis ,chemistry.chemical_compound ,Thioredoxins ,Bacterial Proteins ,In vivo ,Oxidoreductase ,Animals ,Humans ,Enzyme Inhibitors ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Hydrogen Peroxide ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Ligand (biochemistry) ,biology.organism_classification ,Glutathione ,0104 chemical sciences ,Enzyme ,chemistry ,Biochemistry ,Drug Design ,Chemically induced dimerization ,Protein Multimerization ,Oxidoreductases ,Oxidation-Reduction ,Protein Binding - Abstract
Trypanosomal and leishmanial infections claim tens of thousands of lives each year. The metabolism of these unicellular eukaryotic parasites differs from the human host and their enzymes thus constitute promising drug targets. Tryparedoxin (Tpx) from Trypanosoma brucei is the essential oxidoreductase in the parasite's hydroperoxide-clearance cascade. In vitro and in vivo functional assays show that a small, selective inhibitor efficiently inhibits Tpx. With X-ray crystallography, SAXS, analytical SEC, SEC-MALS, MD simulations, ITC, and NMR spectroscopy, we show how covalent binding of this monofunctional inhibitor leads to Tpx dimerization. Intra- and intermolecular inhibitor-inhibitor, protein-protein, and inhibitor-protein interactions stabilize the dimer. The behavior of this efficient antitrypanosomal molecule thus constitutes an exquisite example of chemically induced dimerization with a small, monovalent ligand that can be exploited for future drug design.
- Published
- 2019
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