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Title
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Lactose binding to heat-labile enterotoxin revealed by X-ray crystallography.
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Authors
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T.K.Sixma,
S.E.Pronk,
K.H.Kalk,
B.A.van Zanten,
A.M.Berghuis,
W.G.Hol.
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Ref.
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Nature, 1992,
355,
561-564.
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PubMed id
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Abstract
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Recognition of the oligosaccharide portion of ganglioside GM1 in membranes of
target cells by the heat-labile enterotoxin from Escherichia coli is the crucial
first step in its pathogenesis, as it is for the closely related cholera toxin.
These toxins have five B subunits, which are essential for GM1 binding, and a
single A subunit, which needs to be nicked by proteolysis and reduced, yielding
an A1-'enzyme' and an A2-'linker' peptide. A1 is translocated across the
membrane of intestinal epithelial cells, possibly after endocytosis, upon which
it ADP-ribosylates the G protein Gs alpha. The mechanism of binding and
translocation of these toxins has been extensively investigated, but how the
protein is orientated on binding is still not clear. Knowing the precise
arrangement of the ganglioside binding sites of the toxins will be useful for
designing drugs against the diarrhoeal diseases caused by organisms secreting
these toxins and in the development of oral vaccines against them. We present
here the three-dimensional structure of the E. coli heat-labile enterotoxin
complexed with lactose. This reveals the location of the binding site of the
terminal galactose of GM1, which is consistent with toxin binding to the target
cell with its A1 fragment pointing away from the membrane. A small helix is
identified at the carboxy terminus of A2 which emerges through the central pore
of the B subunits and probably comes into contact with the membrane upon
binding, whereas the A1 subunit is flexible with respect to the B pentamer.
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