Format:
Online-Ressource
ISSN:
1521-3773
Content:
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.
In:
volume:58
In:
number:11
In:
year:2019
In:
pages:3640-3644
In:
extent:5
In:
Angewandte Chemie / International edition. International edition, Weinheim : Wiley-VCH, 1998-, 58, Heft 11 (2019), 3640-3644 (gesamt 5), 1521-3773
Language:
English
DOI:
10.1002/anie.201810470
URN:
urn:nbn:de:101:1-2022073106385740289836
URL:
https://doi.org/10.1002/anie.201810470
URL:
https://nbn-resolving.org/urn:nbn:de:101:1-2022073106385740289836
URL:
https://d-nb.info/1263994628/34
URL:
https://doi.org/10.1002/anie.201810470
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