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PDBsum entry 2qn0
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References listed in PDB file
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Key reference
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Title
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Structural and biochemical studies of botulinum neurotoxin serotype c1 light chain protease: implications for dual substrate specificity.
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Authors
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R.Jin,
S.Sikorra,
C.M.Stegmann,
A.Pich,
T.Binz,
A.T.Brunger.
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Ref.
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Biochemistry, 2007,
46,
10685-10693.
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PubMed id
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Abstract
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Clostridial neurotoxins are the causative agents of the neuroparalytic disease
botulism and tetanus. They block neurotransmitter release through specific
proteolysis of one of the three soluble N-ethylmaleimide-sensitive-factor
attachment protein receptors (SNAREs) SNAP-25, syntaxin, and synaptobrevin,
which constitute part of the synaptic vesicle fusion machinery. The catalytic
component of the clostridial neurotoxins is their light chain (LC), a Zn2+
endopeptidase. There are seven structurally and functionally related botulinum
neurotoxins (BoNTs), termed serotype A to G, and tetanus neurotoxin (TeNT). Each
of them exhibits unique specificity for their target SNAREs and peptide bond(s)
they cleave. The mechanisms of action for substrate recognition and target
cleavage are largely unknown. Here, we report structural and biochemical studies
of BoNT/C1-LC, which is unique among BoNTs in that it exhibits dual specificity
toward both syntaxin and SNAP-25. A distinct pocket (S1') near the active site
likely achieves the correct register for the cleavage site by only allowing Ala
as the P1' residue for both SNAP-25 and syntaxin. Mutations of this SNAP-25
residue dramatically reduce enzymatic activity. The remote alpha-exosite that
was previously identified in the complex of BoNT/A-LC and SNAP-25 is
structurally conserved in BoNT/C1. However, mutagenesis experiments show that
the alpha-exosite of BoNT/C1 plays a less stringent role in substrate
discrimination in comparison to that of BoNT/A, which could account for its dual
substrate specificity.
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