Format

Send to

Choose Destination
Angew Chem Int Ed Engl. 2019 Mar 11;58(11):3640-3644. doi: 10.1002/anie.201810470. Epub 2019 Jan 30.

Inhibitor-Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes.

Author information

1
Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Johann-Joachim-Becherweg 31, 55128, Mainz, Germany.
2
Biomolekulares Magnetresonanz Zentrum (BMRZ), Goethe-Universität Frankfurt, Max-von-Laue Str. 9, 60438, Frankfurt/M, Germany.
3
Institute of Physical and Theoretical Chemistry, Julius-Maximilians-University Würzburg, Emil-Fischer-Straße 42, 97074, Würzburg, Germany.
4
Synchrotron Crystallography Team, EMBL Grenoble Outstation, 71 Avenue des Martyrs, 38042, Grenoble, France.
5
Institute of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, 55128, Mainz, Germany.
6
Rudolf Virchow Center for Experimental Biomedicine, Julius-Maximilians-University Würzburg, Josef-Schneider-Straße 2, Haus D15, 97080, Würzburg, Germany.
7
Biochemistry Center (BZH), Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 328, 69120, Heidelberg, Germany.

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.

KEYWORDS:

African trypanosomes; chemically induced dimerization (CID); covalent inhibitor; oxidoreductase; tryparedoxin

PMID:
30605929
DOI:
10.1002/anie.201810470

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center