4M1U: The Crystal Structure Of Stx2 And A Disaccharide Ligand

Citation:
Abstract
Shiga 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 ability to express the toxin has been acquired by other Escherichia 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 analog of Gb3 bound to the B5 pentamer of Stx2a holotoxin. In this Gb3 analog, alpha-GalNAc replaces the terminal alpha-Gal residue. This co-crystal 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 an attached pyruvate acetal, a ligand for human amyloid P component, and conjugation to poly[acrylamide-co-(3-azidopropylmethacrylamide)] produced a polymer that neutralized Stx2a in a mouse model of Shigatoxemia.
PDB ID: 4M1UDownload
MMDB ID: 115311
PDB Deposition Date: 2013/8/4
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 1.56  Å
Source Organism:
Escherichia coli O157:H7
Similar Structures:
Biological Unit for 4M1U: hexameric; determined by author and by software (PISA)
Molecular Components in 4M1U
Label Count Molecule
Proteins (6 molecules)
1
Shiga Toxin 2 A-subunit
Molecule annotation
5
Shiga Toxin 2 B Subunit
Molecule annotation
Chemicals (7 molecules)
1
3
2
2
3
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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