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==Crystal Structure Analysis of Chitinase A from Vibrio harveyi with novel inhibitors - W275G mutant complex structure with chelerythrine== | |||
<StructureSection load='3as1' size='340' side='right' caption='[[3as1]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3as1]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"achromobacter_harveyi"_johnson_and_shunk_1936 "achromobacter harveyi" johnson and shunk 1936]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AS1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3AS1 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CTI:1,2-DIMETHOXY-12-METHYL[1,3]BENZODIOXOLO[5,6-C]PHENANTHRIDIN-12-IUM'>CTI</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3aro|3aro]], [[3arp|3arp]], [[3arq|3arq]], [[3arr|3arr]], [[3ars|3ars]], [[3art|3art]], [[3aru|3aru]], [[3arv|3arv]], [[3arw|3arw]], [[3arx|3arx]], [[3ary|3ary]], [[3arz|3arz]], [[3as0|3as0]], [[3as2|3as2]], [[3as3|3as3]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CHIA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=669 "Achromobacter harveyi" Johnson and Shunk 1936])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Chitinase Chitinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.14 3.2.1.14] </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=3as1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3as1 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3as1 RCSB], [http://www.ebi.ac.uk/pdbsum/3as1 PDBsum]</span></td></tr> | |||
</table> | |||
<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> | |||
==See Also== | ==See Also== | ||
*[[Chitinase|Chitinase]] | *[[Chitinase|Chitinase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Achromobacter harveyi johnson and shunk 1936]] | [[Category: Achromobacter harveyi johnson and shunk 1936]] | ||
[[Category: Chitinase]] | [[Category: Chitinase]] | ||
[[Category: Pantoom, S | [[Category: Pantoom, S]] | ||
[[Category: Prinz, H | [[Category: Prinz, H]] | ||
[[Category: Suginta, W | [[Category: Suginta, W]] | ||
[[Category: Vetter, I R | [[Category: Vetter, I R]] | ||
[[Category: Glycosidase]] | [[Category: Glycosidase]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
Revision as of 21:33, 21 December 2014
Crystal Structure Analysis of Chitinase A from Vibrio harveyi with novel inhibitors - W275G mutant complex structure with chelerythrineCrystal Structure Analysis of Chitinase A from Vibrio harveyi with novel inhibitors - W275G mutant complex structure with chelerythrine
Structural highlights
Publication 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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