| MECHANISM OF ACTION |
Shiga toxin are made up of 2 subunits. The so-called B subunit binds to mammalian cells, allowing the A subunit to gain entry & do toxin's dirty work. A strain of E. coli has picked up the gene for Shiga toxin, expressing it as the "hamburger toxin" that's proven deadly in undercooked meat Shiga toxin's B subunit is made up of 5 identical monomers, each of which has 3 binding sites with varying affinities for cell surface carbohydrates. The pentamer locks onto cells by gripping > 5 carbohydrate ligands simultaneously. E. coli strain: 0157:H7 |
| TECHNOLOGY |
The researchers sought an inhibitor that would mimic this binding (See Mechanism of Action) approach & latch tenaciously onto the toxin. In designing their molecule, they exploited the crystal structure of the E. coli toxin's B subunit complexed to an analog of its carbohydrate receptor Initially, the team designed a ligand they anticipated might have a high affinity for binding sites 11 angstroem apart on the subunit's monomers. That ligand consisted of 2 trisaccharide units connected by an 11-angstroem-long tether. But the results were disappointing - "almost useless actually". "Then they came up with the idea of attaching the trisaccharide dimer on each of 5 spokes on a core molecule [glucose] in the hopes of 'hitting' 10 binding sites on the 5 monomers". Because of its configuration, the new ligand was dubbed STARFISH Starfish sticks like Velcro to each of the 5 B subunit monomers - but not as expected. Instead of binding to 2 sites per monomer, it binds only to one. Only 5 of Starfish's trisaccharide arms are engaged, leaving the other 5 free to bind another B subunit. The upshot is that Starfish is sandwiched between 2 subunits. |
| UPDATE | 02.00 |
| AUTHOR | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
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