4m1u
From Proteopedia
The crystal structure of Stx2 and a disaccharide ligand
Structural highlights
FunctionPublication Abstract from PubMedShiga toxin type 2 (Stx2a) is clinically most closely associated with enterohemorrhagic E. coli O157:H7-mediated hemorrhagic colitis that sometimes progresses to hemolytic uremic syndrome. The the ability to express the toxin has been acquired by other E. coli strains and outbreaks of food poisoning have caused significant mortality rates as for example in the 2011 outbreak in Northern Germany. Stx2a, an AB5 toxin, gains entry into human cells via the glycosphingolipid receptor Gb3. We have determined the first crystal structure of a disaccharide analogue of Gb3 bound to the B5 pentamer of Stx2a holotoxin. In this Gb3 analogue, alpha-GalNAc replaces the terminal alpha-Gal residue. This molecular structure confirms previous inferences that two of the primary binding sites identified in the B5 pentamer of Stx1 are also functional in Stx2a. This knowledge provides a rationale for the synthesis and evaluation of heterobifunctional antagonists for E. coli toxins that target Stx2a. Incorporation of GalNAc Gb3 trisaccharide in a heterobifunctional ligand with attached pyruvate acetal, a ligand for human amyloid P component, and conjugation to poly[acrylamide-co-(3-azidopropylmeth-acrylamide)] produced a polymer that neutralized Stx2a in a mouse model of Shigatoxemia. The crystal structure of Shiga toxin type 2 with bound disaccharide guides the design of a heterobifunctional toxin inhibitor.,Jacobson JM, Yin J, Kitov PI, Mulvey G, Griener TP, James MN, Armstrong G, Bundle DR J Biol Chem. 2013 Nov 13. PMID:24225957[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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