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==CRYSTAL STRUCTURE OF LEISHMANIA INFANTUM TRYPANOTHIONE REDUCTASE IN COMPLEX WITH NADPH AND TRYPANOTHIONE== | |||
<StructureSection load='4adw' size='340' side='right' caption='[[4adw]], [[Resolution|resolution]] 3.61Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4adw]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Leishmania_infantum Leishmania infantum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ADW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ADW FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GCG:BIS(GAMMA-GLUTAMYL-CYSTEINYL-GLYCINYL)SPERMIDINE'>GCG</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2jk6|2jk6]], [[2w0h|2w0h]], [[2x50|2x50]], [[2yau|2yau]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypanothione-disulfide_reductase Trypanothione-disulfide reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.12 1.8.1.12] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4adw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4adw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4adw RCSB], [http://www.ebi.ac.uk/pdbsum/4adw PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Herein we report a study aimed at discovering a new class of compounds that are able to inhibit Leishmania donovani cell growth. Evaluation of an in-house library of compounds in a whole-cell screening assay highlighted 4-((1-(4-ethylphenyl)-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thi omorpholine (compound 1) as the most active. Enzymatic assays on Leishmania infantum trypanothione reductase (LiTR, belonging to the Leishmania donovani complex) shed light on both the interaction with, and the nature of inhibition by, compound 1. A molecular modeling approach based on docking studies and on the estimation of the binding free energy aided our rationalization of the biological data. Moreover, X-ray crystal structure determination of LiTR in complex with compound 1 confirmed all our results: compound 1 binds to the T(SH)2 binding site, lined by hydrophobic residues such as Trp21 and Met113, as well as residues Glu18 and Tyr110. Analysis of the structure of LiTR in complex with trypanothione shows that Glu18 and Tyr110 are also involved in substrate binding, according to a competitive inhibition mechanism. | |||
Inhibition of Leishmania infantum Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography.,Baiocco P, Poce G, Alfonso S, Cocozza M, Porretta GC, Colotti G, Biava M, Moraca F, Botta M, Yardley V, Fiorillo A, Lantella A, Malatesta F, Ilari A ChemMedChem. 2013 Jun 3. doi: 10.1002/cmdc.201300176. PMID:23733388<ref>PMID:23733388</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Trypanothione reductase|Trypanothione reductase]] | *[[Trypanothione reductase|Trypanothione reductase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Leishmania infantum]] | [[Category: Leishmania infantum]] | ||
[[Category: Trypanothione-disulfide reductase]] | [[Category: Trypanothione-disulfide reductase]] | ||
[[Category: Baiocco, P | [[Category: Baiocco, P]] | ||
[[Category: Colotti, G | [[Category: Colotti, G]] | ||
[[Category: Fiorillo, A | [[Category: Fiorillo, A]] | ||
[[Category: Ilari, A | [[Category: Ilari, A]] | ||
[[Category: Malatesta, F | [[Category: Malatesta, F]] | ||
[[Category: Inhibition mechanism]] | [[Category: Inhibition mechanism]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Revision as of 12:54, 21 December 2014
CRYSTAL STRUCTURE OF LEISHMANIA INFANTUM TRYPANOTHIONE REDUCTASE IN COMPLEX WITH NADPH AND TRYPANOTHIONECRYSTAL STRUCTURE OF LEISHMANIA INFANTUM TRYPANOTHIONE REDUCTASE IN COMPLEX WITH NADPH AND TRYPANOTHIONE
Structural highlights
Publication Abstract from PubMedHerein we report a study aimed at discovering a new class of compounds that are able to inhibit Leishmania donovani cell growth. Evaluation of an in-house library of compounds in a whole-cell screening assay highlighted 4-((1-(4-ethylphenyl)-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thi omorpholine (compound 1) as the most active. Enzymatic assays on Leishmania infantum trypanothione reductase (LiTR, belonging to the Leishmania donovani complex) shed light on both the interaction with, and the nature of inhibition by, compound 1. A molecular modeling approach based on docking studies and on the estimation of the binding free energy aided our rationalization of the biological data. Moreover, X-ray crystal structure determination of LiTR in complex with compound 1 confirmed all our results: compound 1 binds to the T(SH)2 binding site, lined by hydrophobic residues such as Trp21 and Met113, as well as residues Glu18 and Tyr110. Analysis of the structure of LiTR in complex with trypanothione shows that Glu18 and Tyr110 are also involved in substrate binding, according to a competitive inhibition mechanism. Inhibition of Leishmania infantum Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography.,Baiocco P, Poce G, Alfonso S, Cocozza M, Porretta GC, Colotti G, Biava M, Moraca F, Botta M, Yardley V, Fiorillo A, Lantella A, Malatesta F, Ilari A ChemMedChem. 2013 Jun 3. doi: 10.1002/cmdc.201300176. PMID:23733388[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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