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3ds9

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Revision as of 09:20, 14 November 2018

A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than SNAP-25 substrate

Structural highlights

3ds9 is a 2 chain structure with sequence from "bacillus_botulinus"_van_ermengem_1896 "bacillus botulinus" van ermengem 1896. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:	,
Related:	2isg, 1xtf, 3dse
Gene:	botA, CBO0806, CLC_0862 ("Bacillus botulinus" van Ermengem 1896)
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.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Botulinum neurotoxin serotype A is the most lethal of all known toxins. Here, we report the crystal structure, along with SAR data, of the zinc metalloprotease domain of BoNT/A bound to a potent peptidomimetic inhibitor (K(i)=41 nM) that resembles the local sequence of the SNAP-25 substrate. Surprisingly, the inhibitor adopts a helical conformation around the cleavage site, in contrast to the extended conformation of the native substrate. The backbone of the inhibitor's P1 residue displaces the putative catalytic water molecule and concomitantly interacts with the "proton shuttle" E224. This mechanism of inhibition is aided by residue contacts in the conserved S1' pocket of the substrate binding cleft and by the induction of new hydrophobic pockets, which are not present in the apo form, especially for the P2' residue of the inhibitor. Our inhibitor is specific for BoNT/A as it does not inhibit other BoNT serotypes or thermolysin.

A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than SNAP-25 substrate.,Zuniga JE, Schmidt JJ, Fenn T, Burnett JC, Arac D, Gussio R, Stafford RG, Badie SS, Bavari S, Brunger AT Structure. 2008 Oct 8;16(10):1588-97. PMID:18940613^[1]

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

References

↑ Zuniga JE, Schmidt JJ, Fenn T, Burnett JC, Arac D, Gussio R, Stafford RG, Badie SS, Bavari S, Brunger AT. A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than SNAP-25 substrate. Structure. 2008 Oct 8;16(10):1588-97. PMID:18940613 doi:10.1016/j.str.2008.07.011

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3ds9"

@@ Line 1: / Line 1: @@
 ==A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than SNAP-25 substrate==
 <StructureSection load='3ds9' size='340' side='right' caption='[[3ds9]], [[Resolution|resolution]] 1.76&Aring;' scene=''>
@@ Line 8: / Line 9: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">botA, CBO0806, CLC_0862 ([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='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=3ds9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ds9 OCA], [http://pdbe.org/3ds9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ds9 RCSB], [http://www.ebi.ac.uk/pdbsum/3ds9 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=3ds9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ds9 OCA], [http://pdbe.org/3ds9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ds9 RCSB], [http://www.ebi.ac.uk/pdbsum/3ds9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ds9 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 16: / Line 17: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ds/3ds9_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ds/3ds9_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 51: / Line 52: @@
 [[Category: Neurotoxin]]
 [[Category: Neurotransmission]]
+[[Category: Pharmaceutical]]
 [[Category: Protease]]
 [[Category: Secreted]]
@@ Line 56: / Line 58: @@
 [[Category: Toxin]]
 [[Category: Transmembrane]]
+[[Category: Zinc]]

3ds9

From Proteopedia

Revision as of 09:20, 14 November 2018

A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than SNAP-25 substrate

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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