Structural highlights
FunctionTYPX_TRYBB Acts as a thiol-disulfide oxidoreductase. It is spontaneously reduced by trypanothione. Publication Abstract from PubMedTrypanosomal and leishmanial infections claim tens of thousands of lives each year. The metabolism of these single cell 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. Functional in vitro and in vivo assays show that a small, selective inhibitor efficiently inhibits Tpx. By 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. Inhibitor-induced dimerization of an essential oxidoreductase from African Trypanosomes.,Wagner A, Le TA, Brennich M, Klein P, Bader N, Diehl E, Paszek D, Weickhmann AK, Dirdjaja N, Krauth-Siegel RL, Engels B, Opatz T, Schindelin H, Hellmich UA Angew Chem Int Ed Engl. 2019 Jan 3. doi: 10.1002/anie.201810470. PMID:30605929[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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