Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase.

2.50
Hdl Handle:
http://hdl.handle.net/10033/293024
Title:
Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase.
Authors:
Koch, Oliver; Cappel, Daniel; Nocker, Monika; Jäger, Timo; Flohé, Leopold; Sotriffer, Christoph A; Selzer, Paul M
Abstract:
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.
Affiliation:
MSD Animal Health Innovation GmbH, Schwabenheim, Germany. oliver.koch@tu-dortmund.de
Citation:
Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase. 2013, 8 (2):e56788 PLoS ONE
Journal:
PloS one
Issue Date:
2013
URI:
http://hdl.handle.net/10033/293024
DOI:
10.1371/journal.pone.0056788
PubMed ID:
23451087
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
Publications of Scientific Director (GFW)

Full metadata record

DC FieldValue Language
dc.contributor.authorKoch, Oliveren_GB
dc.contributor.authorCappel, Danielen_GB
dc.contributor.authorNocker, Monikaen_GB
dc.contributor.authorJäger, Timoen_GB
dc.contributor.authorFlohé, Leopolden_GB
dc.contributor.authorSotriffer, Christoph Aen_GB
dc.contributor.authorSelzer, Paul Men_GB
dc.date.accessioned2013-05-30T09:14:10Z-
dc.date.available2013-05-30T09:14:10Z-
dc.date.issued2013-
dc.identifier.citationMolecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase. 2013, 8 (2):e56788 PLoS ONEen_GB
dc.identifier.issn1932-6203-
dc.identifier.pmid23451087-
dc.identifier.doi10.1371/journal.pone.0056788-
dc.identifier.urihttp://hdl.handle.net/10033/293024-
dc.description.abstractThe 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen_GB
dc.titleMolecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase.en
dc.typeArticleen
dc.contributor.departmentMSD Animal Health Innovation GmbH, Schwabenheim, Germany. oliver.koch@tu-dortmund.deen_GB
dc.identifier.journalPloS oneen_GB

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