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PDBsum entry 1qnu
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* Residue conservation analysis
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DOI no:
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Nature
403:669-672
(2000)
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PubMed id:
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Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands.
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P.I.Kitov,
J.M.Sadowska,
G.Mulvey,
G.D.Armstrong,
H.Ling,
N.S.Pannu,
R.J.Read,
D.R.Bundle.
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ABSTRACT
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The diseases caused by Shiga and cholera toxins account for the loss of millions
of lives each year. Both belong to the clinically significant subset of
bacterial AB5 toxins consisting of an enzymatically active A subunit that gains
entry to susceptible mammalian cells after oligosaccharide recognition by the B5
homopentamer. Therapies might target the obligatory oligosaccharide-toxin
recognition event, but the low intrinsic affinity of carbohydrate-protein
interactions hampers the development of low-molecular-weight inhibitors. The
toxins circumvent low affinity by binding simultaneously to five or more
cell-surface carbohydrates. Here we demonstrate the use of the crystal structure
of the B5 subunit of Escherichia coli O157:H7 Shiga-like toxin I (SLT-I) in
complex with an analogue of its carbohydrate receptor to design an oligovalent,
water-soluble carbohydrate ligand (named STARFISH), with subnanomolar inhibitory
activity. The in vitro inhibitory activity is 1-10-million-fold higher than that
of univalent ligands and is by far the highest molar activity of any inhibitor
yet reported for Shiga-like toxins I and II. Crystallography of the
STARFISH/Shiga-like toxin I complex explains this activity. Two trisaccharide
receptors at the tips of each of five spacer arms simultaneously engage all five
B subunits of two toxin molecules.
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Selected figure(s)
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Figure 1.
Figure 1: Structures of monomeric and oligomeric Pk inhibitors
of Shiga-like toxins. 1, Pk trisaccharide methyl glycoside; 2,
dimeric bridged Pk trisaccharide; 3, decameric STARFISH.
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Figure 4.
Figure 4: Mode of binding in the STARFISH-SLT-1 complex. a,
Stereo diagram of the crystallographic dimer of B-subunit
pentamers of SLT-I linked by the STARFISH ligand. For the
protein, -strands
are illustrated as broad arrows and -helices
as coiled ribbons. The ligand is shown in a ball-and-stick
representation, with grey bonds connecting atoms of the
carbohydrate component and magenta bonds connecting atoms of the
linker. b, Diagram of half of the STARFISH:SLT-1 B[5] sandwich.
The representation is as in a, except that dashed magenta lines
show a possible conformation for the central component of the
linker, which could not be seen clearly in the electron density.
These figures were drawn with MolScript29 and rendered with
Raster3D^30.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2000,
403,
669-672)
copyright 2000.
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Figures were
selected
by an automated process.
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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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Infect Immun,
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Chem Biol,
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Proc Natl Acad Sci U S A,
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Nat Chem,
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Chembiochem,
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A.V.Pukin,
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Strong inhibition of cholera toxin by multivalent GM1 derivatives.
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Chembiochem,
8,
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B.D.Polizzotti,
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Macromolecules,
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E.Kaltgrad,
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Chembiochem,
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H.M.Branderhorst,
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Strong inhibition of cholera toxin binding by galactose dendrimers.
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Chem Commun (Camb),
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Chembiochem,
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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
codes are
shown on the right.
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}
}
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