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<StructureSection load='5ebk' size='340' side='right' caption='[[5ebk]], [[Resolution|resolution]] 3.51Å' scene=''> | <StructureSection load='5ebk' size='340' side='right' caption='[[5ebk]], [[Resolution|resolution]] 3.51Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5ebk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EBK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EBK FirstGlance]. <br> | <table><tr><td colspan='2'>[[5ebk]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Leiin Leiin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EBK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EBK 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=RDS:6-SEC-BUTOXY-2-[(3-CHLOROPHENYL)SULFANYL]-4-PYRIMIDINAMINE'>RDS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </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=RDS:6-SEC-BUTOXY-2-[(3-CHLOROPHENYL)SULFANYL]-4-PYRIMIDINAMINE'>RDS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2jk6|2jk6]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2jk6|2jk6]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TRYR, LINJ_05_0350 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5671 LEIIN])</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='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=5ebk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ebk OCA], [http://pdbe.org/5ebk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ebk RCSB], [http://www.ebi.ac.uk/pdbsum/5ebk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ebk ProSAT]</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=5ebk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ebk OCA], [http://pdbe.org/5ebk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ebk RCSB], [http://www.ebi.ac.uk/pdbsum/5ebk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ebk ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC50 = 29.43 microM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (Ki 0.25 +/- 0.18 microM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction. | |||
Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives.,Saccoliti F, Angiulli G, Pupo G, Pescatori L, Madia VN, Messore A, Colotti G, Fiorillo A, Scipione L, Gramiccia M, Di Muccio T, Di Santo R, Costi R, Ilari A J Enzyme Inhib Med Chem. 2017 Dec;32(1):304-310. doi:, 10.1080/14756366.2016.1250755. PMID:28098499<ref>PMID:28098499</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5ebk" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Trypanothione reductase|Trypanothione reductase]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Leiin]] | |||
[[Category: Trypanothione-disulfide reductase]] | [[Category: Trypanothione-disulfide reductase]] | ||
[[Category: Angiulli, G]] | [[Category: Angiulli, G]] | ||
[[Category: Ilari, A]] | [[Category: Ilari, A]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Revision as of 09:21, 1 November 2017
Trypanothione reductase in complex with 6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amineTrypanothione reductase in complex with 6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine
Structural highlights
Publication Abstract from PubMedThe study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC50 = 29.43 microM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (Ki 0.25 +/- 0.18 microM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction. Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives.,Saccoliti F, Angiulli G, Pupo G, Pescatori L, Madia VN, Messore A, Colotti G, Fiorillo A, Scipione L, Gramiccia M, Di Muccio T, Di Santo R, Costi R, Ilari A J Enzyme Inhib Med Chem. 2017 Dec;32(1):304-310. doi:, 10.1080/14756366.2016.1250755. PMID:28098499[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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