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PDBsum entry 3dda
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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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Plos Pathog
4:e1000165
(2008)
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PubMed id:
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Substrate binding mode and its implication on drug design for botulinum neurotoxin A.
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D.Kumaran,
R.Rawat,
S.A.Ahmed,
S.Swaminathan.
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ABSTRACT
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The seven antigenically distinct serotypes of Clostridium botulinum neurotoxins,
the causative agents of botulism, block the neurotransmitter release by
specifically cleaving one of the three SNARE proteins and induce flaccid
paralysis. The Centers for Disease Control and Prevention (CDC) has declared
them as Category A biowarfare agents. The most potent among them, botulinum
neurotoxin type A (BoNT/A), cleaves its substrate synaptosome-associated protein
of 25 kDa (SNAP-25). An efficient drug for botulism can be developed only with
the knowledge of interactions between the substrate and enzyme at the active
site. Here, we report the crystal structures of the catalytic domain of BoNT/A
with its uncleavable SNAP-25 peptide (197)QRATKM(202) and its variant
(197)RRATKM(202) to 1.5 A and 1.6 A, respectively. This is the first time the
structure of an uncleavable substrate bound to an active botulinum neurotoxin is
reported and it has helped in unequivocally defining S1 to S5' sites. These
substrate peptides make interactions with the enzyme predominantly by the
residues from 160, 200, 250 and 370 loops. Most notably, the amino nitrogen and
carbonyl oxygen of P1 residue (Gln197) chelate the zinc ion and replace the
nucleophilic water. The P1'-Arg198, occupies the S1' site formed by Arg363,
Thr220, Asp370, Thr215, Ile161, Phe163 and Phe194. The S2' subsite is formed by
Arg363, Asn368 and Asp370, while S3' subsite is formed by Tyr251, Leu256,
Val258, Tyr366, Phe369 and Asn388. P4'-Lys201 makes hydrogen bond with Gln162.
P5'-Met202 binds in the hydrophobic pocket formed by the residues from the 250
and 200 loop. Knowledge of interactions between the enzyme and substrate peptide
from these complex structures should form the basis for design of potent
inhibitors for this neurotoxin.
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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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J.E.Zuniga,
J.T.Hammill,
O.Drory,
J.E.Nuss,
J.C.Burnett,
R.Gussio,
P.Wipf,
S.Bavari,
and
A.T.Brunger
(2010).
Iterative structure-based peptide-like inhibitor design against the botulinum neurotoxin serotype A.
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PLoS One,
5,
e11378.
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PDB code:
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J.Thanongsaksrikul,
P.Srimanote,
S.Maneewatch,
K.Choowongkomon,
P.Tapchaisri,
S.Makino,
H.Kurazono,
and
W.Chaicumpa
(2010).
A V H H that neutralizes the zinc metalloproteinase activity of botulinum neurotoxin type A.
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J Biol Chem,
285,
9657-9666.
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M.Montal
(2010).
Botulinum neurotoxin: a marvel of protein design.
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Annu Rev Biochem,
79,
591-617.
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M.Oshima,
G.B.Leite,
S.Rostelato-Ferreira,
M.A.Da Cruz-Höfling,
L.Rodrigues-Simioni,
and
Y.Oshima-Franco
(2010).
Insights of the effects of polyethylene glycol 400 on mammalian and avian nerve terminals.
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Muscle Nerve,
41,
540-546.
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N.Gul,
L.A.Smith,
and
S.A.Ahmed
(2010).
Light chain separated from the rest of the type a botulinum neurotoxin molecule is the most catalytically active form.
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PLoS One,
5,
e12872.
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R.Agarwal,
J.J.Schmidt,
R.G.Stafford,
and
S.Swaminathan
(2009).
Mode of VAMP substrate recognition and inhibition of Clostridium botulinum neurotoxin F.
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Nat Struct Mol Biol,
16,
789-794.
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PDB codes:
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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
