3qj0

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{{STRUCTURE_3qj0| PDB=3qj0 | SCENE= }}
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==Crystal Structure of BoNT/A LC complexed with Hydroxamate-based Inhibitor PT-3==
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===Crystal Structure of BoNT/A LC complexed with Hydroxamate-based Inhibitor PT-3===
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<StructureSection load='3qj0' size='340' side='right' caption='[[3qj0]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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{{ABSTRACT_PUBMED_21434688}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3qj0]] is a 1 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=3QJ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QJ0 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=QI3:(4R)-4-(4-CHLOROPHENOXY)-1-[(4-CHLOROPHENYL)SULFONYL]-N-HYDROXY-L-PROLINAMIDE'>QI3</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qix|3qix]], [[3qiy|3qiy]], [[3qiz|3qiz]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">botA, CBO0806, CLC_0862, Neurotoxin Light Chain ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1491 Clostridium botulinum])</td></tr>
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<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>
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<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=3qj0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qj0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qj0 RCSB], [http://www.ebi.ac.uk/pdbsum/3qj0 PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Neurotoxins synthesized by Clostridium botulinum bacteria (BoNT), the etiological agent of human botulism, are extremely toxic proteins making them high-risk agents for bioterrorism. Small molecule inhibitor development has been focused on the light chain zinc-dependent metalloprotease domain of the neurotoxin, an effort that has been hampered by its relatively flexible active site. Developed in concert with structure-activity relationship studies, the X-ray crystal structures of the complex of BoNT serotype A light chain (BoNT/A LC) with three different micromolar potency hydroxamate-based inhibitors are reported here for the first time. Comparison with an unliganded BoNT/A LC structure reveals significant changes in the active site as a result of binding by the unique inhibitor scaffolds. The 60/70 loop at the opening of the active site pocket undergoes the largest conformational change, presumably through an induced-fit mechanism, resulting in the most compact catalytic pocket observed in all known BoNT/A LC structures.
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==Function==
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Structural Characterization of Three Novel Hydroxamate-based Zinc Chelating Inhibitors of the C. botulinum Serotype A Neurotoxin Light Chain Metalloprotease Reveals a Compact Binding Site Resulting from 60/70 Loop Flexibility.,Thompson AA, Jiao GS, Kim S, Thai A, Cregar-Hernandez L, Margosiak SA, Johnson AT, Han GW, O'Malley S, Stevens RC Biochemistry. 2011 Mar 24. PMID:21434688<ref>PMID:21434688</ref>
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[[http://www.uniprot.org/uniprot/BXA1_CLOBH BXA1_CLOBH]] 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.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3qj0]] is a 1 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=3QJ0 OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:021434688</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Bontoxilysin]]
[[Category: Bontoxilysin]]
[[Category: Clostridium botulinum]]
[[Category: Clostridium botulinum]]
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[[Category: Han, G W.]]
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[[Category: Han, G W]]
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[[Category: Stevens, R C.]]
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[[Category: Stevens, R C]]
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[[Category: Thompson, A A.]]
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[[Category: Thompson, A A]]
[[Category: Bont]]
[[Category: Bont]]
[[Category: Botulinum]]
[[Category: Botulinum]]

Revision as of 11:02, 19 December 2014

Crystal Structure of BoNT/A LC complexed with Hydroxamate-based Inhibitor PT-3

3qj0, resolution 2.30Å

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