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Molecular Dynamics Reveal Binding Mode of Glutathionylspermidine by Trypanothione Synthetase
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-131070
- 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 insightsThe 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.…
Autor(en): | Oliver Koch, Daniel Cappel, Monika Nocker, Timo Jäger, Leopold Flohé, Christoph A. Sotriffer, Paul M. Selzer |
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URN: | urn:nbn:de:bvb:20-opus-131070 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Fakultät für Chemie und Pharmazie / Institut für Pharmazie und Lebensmittelchemie |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | PLoS ONE |
Erscheinungsjahr: | 2013 |
Band / Jahrgang: | 8 |
Heft / Ausgabe: | 2 |
Seitenangabe: | e56788 |
Originalveröffentlichung / Quelle: | PLoS ONE 8(2): e56788. doi:10.1371/journal.pone.0056788 |
DOI: | https://doi.org/10.1371/journal.pone.0056788 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 615 Pharmakologie, Therapeutik |
Freie Schlagwort(e): | RESP model; biosynthesis; brucei; chemotherapy; crithidia fasciulata; leishmaniasis; metabolism; purification; system; trypanosoma cruzi |
Datum der Freischaltung: | 12.05.2016 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung |