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PDBsum entry 4hev
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Hydrolase/hydrolase inhibitor
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PDB id
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4hev
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Clostridium botulinum serotype a light chain inhibited by adamantane hydroxamate
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Structure:
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Botulinum neurotoxin type a light chain. Chain: a, b. Fragment: unp residues 1-425. Synonym: bont/a, bontoxilysin-a, botox. Engineered: yes
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Source:
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Clostridium botulinum. Organism_taxid: 1491. Gene: bota, atx, bna. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.50Å
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R-factor:
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0.204
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R-free:
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0.248
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Authors:
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N.R.Silvaggi,K.N.Allen
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Key ref:
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P.Šilhár
et al.
(2013).
Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.
Bioorg Med Chem Lett,
21,
1344-1348.
PubMed id:
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Date:
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04-Oct-12
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Release date:
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23-Jan-13
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PROCHECK
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Headers
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References
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P0DPI1
(BXA1_CLOBH) -
Botulinum neurotoxin type A from Clostridium botulinum (strain Hall / ATCC 3502 / NCTC 13319 / Type A)
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Seq:
Struc:
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1296 a.a.
397 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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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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Bioorg Med Chem Lett
21:1344-1348
(2013)
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PubMed id:
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Evaluation of adamantane hydroxamates as botulinum neurotoxin inhibitors: synthesis, crystallography, modeling, kinetic and cellular based studies.
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P.Šilhár,
N.R.Silvaggi,
S.Pellett,
K.Čapková,
E.A.Johnson,
K.N.Allen,
K.D.Janda.
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ABSTRACT
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Botulinum neurotoxins (BoNTs) are the most lethal biotoxins known to mankind and
are responsible for the neuroparalytic disease botulism. Current treatments for
botulinum poisoning are all protein based and thus have a limited window of
treatment opportunity. Inhibition of the BoNT light chain protease (LC) has
emerged as a therapeutic strategy for the treatment of botulism as it may
provide an effective post exposure remedy. Using a combination of
crystallographic and modeling studies a series of hydroxamates derived from
1-adamantylacetohydroxamic acid (3a) were prepared. From this group of
compounds, an improved potency of about 17-fold was observed for two
derivatives. Detailed mechanistic studies on these structures revealed a
competitive inhibition model, with a K(i)=27 nM, which makes these compounds
some of the most potent small molecule, non-peptidic BoNT/A LC inhibitors
reported to date.
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Links
