Structure of the shiga-like toxin I B-pentamer complexed with an analogue of its receptor Gb3.
Shiga-like toxin I (SLT-I) is a virulence factor of Escherichia coli strains that cause disease in humans. Like other members of the Shiga toxin family, it consists of an enzymatic (A) subunit and five copies of a binding subunit (the B-pentamer). The B-pentamer binds to a specific glycolipid, globotriaosylceramide (Gb3), on the surface of target cells and thereby plays a crucial role in the entry of the toxin. Here we present the crystal structure at 2.8 A resolution of the SLT-I B-pentamer complexed with an analogue of the Gb3 trisaccharide. The structure reveals a surprising density of binding sites, with three trisaccharide molecules bound to each B-subunit monomer of 69 residues. All 15 trisaccharides bind to one side of the B-pentamer, providing further evidence that this side faces the cell membrane. The structural model is consistent with data from site-directed mutagenesis and binding of carbohydrate analogues, and allows the rational design of therapeutic Gb3 analogues that block the attachment of toxin to cells.
Ling
H
H
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Boodhoo
A
A
Hazes
B
B
Cummings
M D
MD
Armstrong
G D
GD
Brunton
J L
JL
Read
R J
RJ
D001427:Bacterial Toxins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004768:Enterotoxins / Q000737:chemistry; D004926:Escherichia coli / Q000737:chemistry; D046911:Macromolecular Substances; D008958:Models, Molecular; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D022622:Shiga Toxin 1; D014281:Trihexosylceramides / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology
D001427:Bacterial Toxins; D004768:Enterotoxins; D046911:Macromolecular Substances; D011956:Receptors, Cell Surface; D022622:Shiga Toxin 1; D014281:Trihexosylceramides; C018549:globotriaosylceramide