Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase.
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Authors
Koch, OliverCappel, Daniel
Nocker, Monika
Jäger, Timo
Flohé, Leopold
Sotriffer, Christoph A
Selzer, Paul M
Issue Date
2013
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Show full item recordAbstract
The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two Mg(2+) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows N(1)-glutathionylation of N(8)-glutathionylspermidine, classifying N(8)-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for N(8)-glutathionylspermidine was characterised as druggable.Citation
Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase. 2013, 8 (2):e56788 PLoS ONEAffiliation
MSD Animal Health Innovation GmbH, Schwabenheim, Germany. oliver.koch@tu-dortmund.deJournal
PloS onePubMed ID
23451087Type
ArticleLanguage
enISSN
1932-6203ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0056788
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