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==Crystal Structure Analysis of Chitinase A from Vibrio harveyi with novel inhibitors - W275G mutant complex structure with 2-(imidazolin-2-yl)-5-isothiocyanatobenzofuran== | |||
<StructureSection load='3as3' size='340' side='right'caption='[[3as3]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3as3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Vibrio_harveyi Vibrio harveyi]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3AS3 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=I5I:2-(5-ISOTHIOCYANATO-1-BENZOFURAN-2-YL)-4,5-DIHYDRO-1H-IMIDAZOLE'>I5I</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=3as3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3as3 OCA], [https://pdbe.org/3as3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3as3 RCSB], [https://www.ebi.ac.uk/pdbsum/3as3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3as3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q9AMP1_VIBHA Q9AMP1_VIBHA] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Six novel inhibitors of Vibrio harveyi chitinase A (VhChiA), a family-18 chitinase homolog, were identified by in vitro screening of a library of pharmacologically active compounds. Unlike the previously identified inhibitors that mimicked the reaction intermediates, crystallographic evidence from 14 VhChiA-inhibitor complexes showed that all of the inhibitor molecules occupied the outer part of the substrate-binding cleft at two hydrophobic areas. The interactions at the aglycone location are well defined and tightly associated with Trp-397 and Trp-275, whereas the interactions at the glycone location are patchy, indicating lower affinity and a loose interaction with two consensus residues, Trp-168 and Val-205. When Trp-275 was substituted with glycine (W275G), the binding affinity toward all of the inhibitors dramatically decreased, and in most structures two inhibitor molecules were found to stack against Trp-397 at the aglycone site. Such results indicate that hydrophobic interactions are important for binding of the newly identified inhibitors by the chitinase. X-ray data and isothermal microcalorimetry showed that the inhibitors occupied the active site of VhChiA in three different binding modes, including single-site binding, independent two-site binding, and sequential two-site binding. The inhibitory effect of dequalinium in the low nanomolar range makes this compound an extremely attractive lead compound for plausible development of therapeutics against human diseases involving chitinase-mediated pathologies. | |||
Potent family-18 chitinase inhibitors: x-ray structures, affinities, and binding mechanisms.,Pantoom S, Vetter IR, Prinz H, Suginta W J Biol Chem. 2011 Jul 8;286(27):24312-23. Epub 2011 Apr 29. PMID:21531720<ref>PMID:21531720</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3as3" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Chitinase|Chitinase]] | *[[Chitinase 3D structures|Chitinase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Vibrio harveyi]] | [[Category: Vibrio harveyi]] | ||
[[Category: Pantoom | [[Category: Pantoom S]] | ||
[[Category: Prinz | [[Category: Prinz H]] | ||
[[Category: Suginta | [[Category: Suginta W]] | ||
[[Category: Vetter | [[Category: Vetter IR]] | ||
Latest revision as of 18:53, 4 October 2023
Crystal Structure Analysis of Chitinase A from Vibrio harveyi with novel inhibitors - W275G mutant complex structure with 2-(imidazolin-2-yl)-5-isothiocyanatobenzofuranCrystal Structure Analysis of Chitinase A from Vibrio harveyi with novel inhibitors - W275G mutant complex structure with 2-(imidazolin-2-yl)-5-isothiocyanatobenzofuran
Structural highlights
FunctionPublication Abstract from PubMedSix novel inhibitors of Vibrio harveyi chitinase A (VhChiA), a family-18 chitinase homolog, were identified by in vitro screening of a library of pharmacologically active compounds. Unlike the previously identified inhibitors that mimicked the reaction intermediates, crystallographic evidence from 14 VhChiA-inhibitor complexes showed that all of the inhibitor molecules occupied the outer part of the substrate-binding cleft at two hydrophobic areas. The interactions at the aglycone location are well defined and tightly associated with Trp-397 and Trp-275, whereas the interactions at the glycone location are patchy, indicating lower affinity and a loose interaction with two consensus residues, Trp-168 and Val-205. When Trp-275 was substituted with glycine (W275G), the binding affinity toward all of the inhibitors dramatically decreased, and in most structures two inhibitor molecules were found to stack against Trp-397 at the aglycone site. Such results indicate that hydrophobic interactions are important for binding of the newly identified inhibitors by the chitinase. X-ray data and isothermal microcalorimetry showed that the inhibitors occupied the active site of VhChiA in three different binding modes, including single-site binding, independent two-site binding, and sequential two-site binding. The inhibitory effect of dequalinium in the low nanomolar range makes this compound an extremely attractive lead compound for plausible development of therapeutics against human diseases involving chitinase-mediated pathologies. Potent family-18 chitinase inhibitors: x-ray structures, affinities, and binding mechanisms.,Pantoom S, Vetter IR, Prinz H, Suginta W J Biol Chem. 2011 Jul 8;286(27):24312-23. Epub 2011 Apr 29. PMID:21531720[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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