3qiz

From Proteopedia

(Difference between revisions)

Revision as of 07:35, 5 August 2016

Crystal Structure of BoNT/A LC complexed with Hydroxamate-based Inhibitor PT-2

Structural highlights

3qiz is a 1 chain structure with sequence from Clobh. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	3qix, 3qiy, 3qj0
Gene:	botA, CBO0806, CLC_0862, Neurotoxin Light Chain (CLOBH)
Activity:	Bontoxilysin, with EC number 3.4.24.69
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.

Publication Abstract from PubMed

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.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Thompson AA, Jiao GS, Kim S, Thai A, Cregar-Hernandez L, Margosiak SA, Johnson AT, Han GW, O'Malley S, Stevens RC. 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. Biochemistry. 2011 Mar 24. PMID:21434688 doi:10.1021/bi2001483

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3qiz"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of BoNT/A LC complexed with Hydroxamate-based Inhibitor PT-2==
 <StructureSection load='3qiz' size='340' side='right' caption='[[3qiz]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3qiz]] 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=3QIZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QIZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3qiz]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Clobh Clobh]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QIZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QIZ FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=QI2:(2S,4R)-2-(2-{[3-(4-FLUORO-3-METHYLPHENYL)PROPYL](METHYL)AMINO}ETHYL)-4-(4-FLUOROPHENYL)-N-HYDROXY-4-METHOXYBUTANAMIDE'>QI2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qix|3qix]], [[3qiy|3qiy]], [[3qj0|3qj0]]</td></tr>
-<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>
+<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=441771 CLOBH])</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=3qiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qiz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qiz RCSB], [http://www.ebi.ac.uk/pdbsum/3qiz 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=3qiz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qiz OCA], [http://pdbe.org/3qiz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qiz RCSB], [http://www.ebi.ac.uk/pdbsum/3qiz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qiz ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3qiz" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Botulinum neurotoxin|Botulinum neurotoxin]]
 == References ==
 <references/>
@@ Line 24: / Line 29: @@
 </StructureSection>
 [[Category: Bontoxilysin]]
-[[Category: Clostridium botulinum]]
+[[Category: Clobh]]
 [[Category: Han, G W]]
 [[Category: Stevens, R C]]

3qiz

From Proteopedia

Revision as of 07:35, 5 August 2016

Crystal Structure of BoNT/A LC complexed with Hydroxamate-based Inhibitor PT-2

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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