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PDBsum entry 2imc
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References listed in PDB file
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Key reference
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Title
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Structures of clostridium botulinum neurotoxin serotype a light chain complexed with small-Molecule inhibitors highlight active-Site flexibility.
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Authors
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N.R.Silvaggi,
G.E.Boldt,
M.S.Hixon,
J.P.Kennedy,
S.Tzipori,
K.D.Janda,
K.N.Allen.
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Ref.
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Chem Biol, 2007,
14,
533-542.
[DOI no: ]
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PubMed id
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Abstract
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The potential for the use of Clostridial neurotoxins as bioweapons makes the
development of small-molecule inhibitors of these deadly toxins a top priority.
Recently, screening of a random hydroxamate library identified a small-molecule
inhibitor of C. botulinum Neurotoxin Serotype A Light Chain (BoNT/A-LC),
4-chlorocinnamic hydroxamate, a derivative of which has been shown to have in
vivo efficacy in mice and no toxicity. We describe the X-ray crystal structures
of BoNT/A-LC in complexes with two potent small-molecule inhibitors. The
structures of the enzyme with 4-chlorocinnamic hydroxamate or
2,4-dichlorocinnamic hydroxamate bound are compared to the structure of the
enzyme complexed with L-arginine hydroxamate, an inhibitor with modest affinity.
Taken together, this suite of structures provides surprising insights into the
BoNT/A-LC active site, including unexpected conformational flexibility at the
S1' site that changes the electrostatic environment of the binding pocket.
Information gained from these structures will inform the design and optimization
of more effective small-molecule inhibitors of BoNT/A-LC.
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Figure 2.
Figure 2. Chemical Structures of the Compounds Used in This
Study
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Figure 4.
Figure 4. Structures of BoNT/A-LC(1–424) Bound to
Hydroxamate Inhibitors
Stereo representations of the three
enzyme-inhibitor complexes ([A], LC:1; [B], LC:2; [C], LC:3)
showing the unweighted 2|F[o]| − |F[c]| simulated annealing
composite omit electron-density maps (green mesh) for the
inhibitor and residues 366–372 (the 370 loop) contoured at
1.25σ. Active-site residues are represented as cylinders with
gray carbon atoms. The inhibitors are shown in ball-and-stick
representation with brass carbons. The catalytic Zn(II) ions are
rendered as metallic spheres. This figure was rendered using
POVScript+ [48] and [49] and POVRAY (www.povray.org).
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The above figures are
reprinted
by permission from Cell Press:
Chem Biol
(2007,
14,
533-542)
copyright 2007.
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