4apn: Difference between revisions
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==Structure of TR from Leishmania infantum in complex with a diarylpirrole-based inhibitor== | ==Structure of TR from Leishmania infantum in complex with a diarylpirrole-based inhibitor== | ||
<StructureSection load='4apn' size='340' side='right' caption='[[4apn]], [[Resolution|resolution]] 3.20Å' scene=''> | <StructureSection load='4apn' size='340' side='right'caption='[[4apn]], [[Resolution|resolution]] 3.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4apn]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4apn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_infantum Leishmania infantum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4APN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4APN 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=JV0:4-[[1-(4-ETHYLPHENYL)-2-METHYL-5-(4-METHYLSULFANYLPHENYL)PYRROL-3-YL]METHYL]THIOMORPHOLINE'>JV0</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=JV0:4-[[1-(4-ETHYLPHENYL)-2-METHYL-5-(4-METHYLSULFANYLPHENYL)PYRROL-3-YL]METHYL]THIOMORPHOLINE'>JV0</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4apn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4apn OCA], [https://pdbe.org/4apn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4apn RCSB], [https://www.ebi.ac.uk/pdbsum/4apn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4apn ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/A4HSF7_LEIIN A4HSF7_LEIIN] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 25: | Line 26: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Leishmania infantum]] | ||
[[Category: Baiocco | [[Category: Baiocco P]] | ||
[[Category: Biava | [[Category: Biava M]] | ||
[[Category: Colotti | [[Category: Colotti G]] | ||
[[Category: Ilari | [[Category: Ilari A]] | ||
Latest revision as of 14:32, 20 December 2023
Structure of TR from Leishmania infantum in complex with a diarylpirrole-based inhibitorStructure of TR from Leishmania infantum in complex with a diarylpirrole-based inhibitor
Structural highlights
FunctionPublication 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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