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==Clostridium Botulinum Serotype A Light Chain Inhibited By Adamantane Hydroxamate== | |||
<StructureSection load='4hev' size='340' side='right' caption='[[4hev]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4hev]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Clostridium_botulinum Clostridium botulinum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HEV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HEV FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AXM:N-HYDROXY-2-[(3S,5S,7S)-TRICYCLO[3.3.1.1~3,7~]DEC-1-YL]ACETAMIDE'>AXM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">botA, atx, bna ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1491 Clostridium botulinum])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Bontoxilysin Bontoxilysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.69 3.4.24.69] </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=4hev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hev OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hev RCSB], [http://www.ebi.ac.uk/pdbsum/4hev PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Botulinum neurotoxins (BoNTs) are the most lethal biotoxins known to mankind and are responsible for the neuroparalytic disease botulism. Current treatments for botulinum poisoning are all protein based and thus have a limited window of treatment opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a therapeutic strategy for the treatment of botulism as it may provide an effective post exposure remedy. Using a combination of crystallographic and modeling studies a series of hydroxamates derived from 1-adamantylacetohydroxamic acid (3a) were prepared. From this group of compounds, an improved potency of about 17-fold was observed for two derivatives. Detailed mechanistic studies on these structures revealed a competitive inhibition model, with a K(i)=27 nM, which makes these compounds some of the most potent small molecule, non-peptidic BoNT/A LC inhibitors reported to date. | |||
Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.,Silhar P, Silvaggi NR, Pellett S, Capkova K, Johnson EA, Allen KN, Janda KD Bioorg Med Chem. 2013 Mar 1;21(5):1344-8. doi: 10.1016/j.bmc.2012.12.001. Epub, 2012 Dec 20. PMID:23340139<ref>PMID:23340139</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bontoxilysin]] | [[Category: Bontoxilysin]] | ||
[[Category: Clostridium botulinum]] | [[Category: Clostridium botulinum]] | ||
[[Category: Allen, K N | [[Category: Allen, K N]] | ||
[[Category: Silvaggi, N R | [[Category: Silvaggi, N R]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Zn2+-dependent metalloprotease]] | [[Category: Zn2+-dependent metalloprotease]] | ||
Revision as of 15:27, 21 December 2014
Clostridium Botulinum Serotype A Light Chain Inhibited By Adamantane HydroxamateClostridium Botulinum Serotype A Light Chain Inhibited By Adamantane Hydroxamate
Structural highlights
Publication Abstract from PubMedBotulinum neurotoxins (BoNTs) are the most lethal biotoxins known to mankind and are responsible for the neuroparalytic disease botulism. Current treatments for botulinum poisoning are all protein based and thus have a limited window of treatment opportunity. Inhibition of the BoNT light chain protease (LC) has emerged as a therapeutic strategy for the treatment of botulism as it may provide an effective post exposure remedy. Using a combination of crystallographic and modeling studies a series of hydroxamates derived from 1-adamantylacetohydroxamic acid (3a) were prepared. From this group of compounds, an improved potency of about 17-fold was observed for two derivatives. Detailed mechanistic studies on these structures revealed a competitive inhibition model, with a K(i)=27 nM, which makes these compounds some of the most potent small molecule, non-peptidic BoNT/A LC inhibitors reported to date. Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.,Silhar P, Silvaggi NR, Pellett S, Capkova K, Johnson EA, Allen KN, Janda KD Bioorg Med Chem. 2013 Mar 1;21(5):1344-8. doi: 10.1016/j.bmc.2012.12.001. Epub, 2012 Dec 20. PMID:23340139[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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