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PDBsum entry 1g9c
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.24.69
- bontoxilysin.
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Reaction:
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Limited hydrolysis of proteins of the neuroexocytosis apparatus, synaptobrevins, SNAP25 or syntaxin. No detected action on small molecule substrates.
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Cofactor:
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Zn(2+)
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DOI no:
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Biochemistry
41:9795-9802
(2002)
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PubMed id:
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A novel mechanism for Clostridium botulinum neurotoxin inhibition.
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S.Eswaramoorthy,
D.Kumaran,
S.Swaminathan.
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ABSTRACT
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Clostridium botulinum neurotoxins are zinc endopeptidase proteins responsible
for cleaving specific peptide bonds of proteins of neuroexocytosis apparatus.
The ability of drugs to interfere with toxin's catalytic activity is being
evaluated with zinc chelators and metalloprotease inhibitors. It is important to
develop effective pharmacological treatment for the intact holotoxin before the
catalytic domain separates and enters the cytosol. We present here evidence for
a novel mechanism of an inhibitor binding to the holotoxin and for the chelation
of zinc from our structural studies on Clostridium botulinum neurotoxin type B
in complex with a potential metalloprotease inhibitor,
bis(5-amidino-2-benzimidazolyl)methane, and provide snapshots of the reaction as
it progresses. The binding and inhibition mechanism of this inhibitor to the
neurotoxin seems to be unique for intact botulinum neurotoxins. The environment
of the active site rearranges in the presence of the inhibitor, and the zinc ion
is gradually removed from the active site and transported to a different site in
the protein, probably causing loss of catalytic activity.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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B.R.Singh
(2006).
Botulinum neurotoxin structure, engineering, and novel cellular trafficking and targeting.
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Neurotox Res,
9,
73-92.
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J.C.Burnett,
E.A.Henchal,
A.L.Schmaljohn,
and
S.Bavari
(2005).
The evolving field of biodefence: therapeutic developments and diagnostics.
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Nat Rev Drug Discov,
4,
281-297.
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R.Kukreja,
and
B.Singh
(2005).
Biologically active novel conformational state of botulinum, the most poisonous poison.
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J Biol Chem,
280,
39346-39352.
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B.Segelke,
M.Knapp,
S.Kadkhodayan,
R.Balhorn,
and
B.Rupp
(2004).
Crystal structure of Clostridium botulinum neurotoxin protease in a product-bound state: Evidence for noncanonical zinc protease activity.
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Proc Natl Acad Sci U S A,
101,
6888-6893.
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PDB code:
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J.J.Schmidt,
and
R.G.Stafford
(2003).
Fluorigenic substrates for the protease activities of botulinum neurotoxins, serotypes A, B, and F.
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Appl Environ Microbiol,
69,
297-303.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
