6dkk

From Proteopedia

(Difference between revisions)

Revision as of 10:11, 18 December 2019

Structure of BoNT

Structural highlights

6dkk is a 2 chain structure with sequence from Clob1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	botA, atx, bna (CLOB1)
Activity:	Bontoxilysin, with EC number 3.4.24.69
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Botulinum neurotoxin (BoNT) delivers its protease domain across the vesicle membrane to enter the neuronal cytosol upon vesicle acidification. This process is mediated by its translocation domain (HN), but the molecular mechanism underlying membrane insertion of HN remains poorly understood. Here, we report two crystal structures of BoNT/A1 HN that reveal a novel molecular switch (termed BoNT-switch) in HN, where buried alpha-helices transform into surface-exposed hydrophobic beta-hairpins triggered by acidic pH. Locking the BoNT-switch by disulfide trapping inhibited the association of HN with anionic liposomes, blocked channel formation by HN, and reduced the neurotoxicity of BoNT/A1 by up to ~180-fold. Single particle counting studies showed that an acidic environment tends to promote BoNT/A1 self-association on liposomes, which is partly regulated by the BoNT-switch. These findings suggest that the BoNT-switch flips out upon exposure to the acidic endosomal pH, which enables membrane insertion of HN that subsequently leads to LC delivery.

A viral-fusion-peptide-like molecular switch drives membrane insertion of botulinum neurotoxin A1.,Lam KH, Guo Z, Krez N, Matsui T, Perry K, Weisemann J, Rummel A, Bowen ME, Jin R Nat Commun. 2018 Dec 18;9(1):5367. doi: 10.1038/s41467-018-07789-4. PMID:30560862^[1]

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

References

↑ Lam KH, Guo Z, Krez N, Matsui T, Perry K, Weisemann J, Rummel A, Bowen ME, Jin R. A viral-fusion-peptide-like molecular switch drives membrane insertion of botulinum neurotoxin A1. Nat Commun. 2018 Dec 18;9(1):5367. doi: 10.1038/s41467-018-07789-4. PMID:30560862 doi:http://dx.doi.org/10.1038/s41467-018-07789-4

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/6dkk"

@@ Line 1: / Line 1: @@
 ==Structure of BoNT==
-<StructureSection load='6dkk' size='340' side='right' caption='[[6dkk]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+<StructureSection load='6dkk' size='340' side='right'caption='[[6dkk]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6dkk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DKK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DKK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6dkk]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Clob1 Clob1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DKK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DKK FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=441770 CLOB1])</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=6dkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dkk OCA], [http://pdbe.org/6dkk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dkk RCSB], [http://www.ebi.ac.uk/pdbsum/6dkk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dkk ProSAT]</span></td></tr>
@@ Line 19: / Line 20: @@
 </div>
 <div class="pdbe-citations 6dkk" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Botulinum neurotoxin 3D structures|Botulinum neurotoxin 3D structures]]
 == References ==
 <references/>
@@ Line 24: / Line 28: @@
 </StructureSection>
 [[Category: Bontoxilysin]]
+[[Category: Clob1]]
+[[Category: Large Structures]]
 [[Category: Jin, R]]
 [[Category: Lam, K]]

6dkk

From Proteopedia

Revision as of 10:11, 18 December 2019

Structure of BoNT

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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