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Inhibitor‐Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes
Author(s) -
Wagner Annika,
Le Thien Anh,
Brennich Martha,
Klein Philipp,
Bader Nicole,
Diehl Erika,
Paszek Daniel,
Weickhmann A. Katharina,
Dirdjaja Natalie,
KrauthSiegel R. Luise,
Engels Bernd,
Opatz Till,
Schindelin Hermann,
Hellmich Ute A.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201810470
Subject(s) - oxidoreductase , chemistry , dimer , small molecule , drug discovery , biochemistry , small angle x ray scattering , enzyme , in vivo , stereochemistry , biology , physics , microbiology and biotechnology , organic chemistry , scattering , optics
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.