4hev: Difference between revisions
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==Clostridium Botulinum Serotype A Light Chain Inhibited By Adamantane Hydroxamate== | ==Clostridium Botulinum Serotype A Light Chain Inhibited By Adamantane Hydroxamate== | ||
<StructureSection load='4hev' size='340' side='right' caption='[[4hev]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='4hev' size='340' side='right' caption='[[4hev]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4hev]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[4hev]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_botulinus"_van_ermengem_1896 "bacillus botulinus" van ermengem 1896]. 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> | </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 | <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 "Bacillus botulinus" van Ermengem 1896])</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='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> | <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://pdbe.org/4hev PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hev RCSB], [http://www.ebi.ac.uk/pdbsum/4hev PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hev ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4hev" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Botulinum neurotoxin|Botulinum neurotoxin]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bacillus botulinus van ermengem 1896]] | |||
[[Category: Bontoxilysin]] | [[Category: Bontoxilysin]] | ||
[[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 21:36, 5 August 2016
Clostridium Botulinum Serotype A Light Chain Inhibited By Adamantane HydroxamateClostridium Botulinum Serotype A Light Chain Inhibited By Adamantane Hydroxamate
Structural highlights
Function[BXA1_CLOBO] Inhibits acetylcholine release. The botulinum toxin binds with high affinity to peripheral neuronal presynaptic membrane to the secretory vesicle protein SV2. It binds directly to the largest luminal loop of SV2A, SV2B and SV2C. It is then internalized by receptor-mediated endocytosis. The C-terminus of the heavy chain (H) is responsible for the adherence of the toxin to the cell surface while the N-terminus mediates transport of the light chain from the endocytic vesicle to the cytosol. After translocation, the light chain (L) hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP-25, thereby blocking neurotransmitter release. Inhibition of acetylcholine release results in flaccid paralysis, with frequent heart or respiratory failure. 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. See AlsoReferences
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