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PDBsum entry 2np0
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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 basis of cell surface receptor recognition by botulinum neurotoxin b.
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Authors
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Q.Chai,
J.W.Arndt,
M.Dong,
W.H.Tepp,
E.A.Johnson,
E.R.Chapman,
R.C.Stevens.
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Ref.
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Nature, 2006,
444,
1096-1100.
[DOI no: ]
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PubMed id
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Abstract
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Botulinum neurotoxins (BoNTs) are potent bacterial toxins that cause paralysis
at femtomolar concentrations by blocking neurotransmitter release. A 'double
receptor' model has been proposed in which BoNTs recognize nerve terminals via
interactions with both gangliosides and protein receptors that mediate their
entry. Of seven BoNTs (subtypes A-G), the putative receptors for BoNT/A, BoNT/B
and BoNT/G have been identified, but the molecular details that govern
recognition remain undefined. Here we report the crystal structure of
full-length BoNT/B in complex with the synaptotagmin II (Syt-II) recognition
domain at 2.6 A resolution. The structure of the complex reveals that Syt-II
forms a short helix that binds to a hydrophobic groove within the binding domain
of BoNT/B. In addition, mutagenesis of amino acid residues within this interface
on Syt-II affects binding of BoNT/B. Structural and sequence analysis reveals
that this hydrophobic groove is conserved in the BoNT/G and BoNT/B subtypes, but
varies in other clostridial neurotoxins. Furthermore, molecular docking studies
using the ganglioside G(T1b) indicate that its binding site is more extensive
than previously proposed and might form contacts with both BoNT/B and
synaptotagmin. The results provide structural insights into how BoNTs recognize
protein receptors and reveal a promising target for blocking toxin-receptor
recognition.
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Figure 1.
Figure 1: The structure of BoNT/B–Syt-II recognition domain
complex. Ribbon diagram of BoNT/B–Syt-II recognition domain
complex, with subdomains of BoNT/B labelled as light chain
(orange), H[N] (green), H[CN] (grey), and H[CC] (blue). The
Syt-II recognition domain (residues 45–59, magenta) forms an
 -helix
when complexed with BoNT/B.
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Figure 2.
Figure 2: Interaction between the H[CC] domain of BoNT/B and the
recognition domain of Syt-II. a, Binding interface on BoNT/B
(circled in dashed line) reveals hydrophobic groove (green,
hydrophobic surface). b, Close-up view of the binding interface
of Syt-II (magenta) and BoNT/B (light blue) by rotating 90°
around the x axis. c, Truncation mutants of Syt-II were tested
for BoNT/B binding activity. d, Point mutants of Syt-II were
tested for BoNT/B binding activity. e, f, Various synaptotagmin
mutants, in which residues within the recognition domain were
interconverted between Syt-II and Syt-I, were tested for BoNT/B
binding activity. WT, wild type; GST, glutathione S-transferase.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2006,
444,
1096-1100)
copyright 2006.
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