1lt6

HEAT-LABILE ENTEROTOXIN B-PENTAMER COMPLEXED WITH METANITROPHENYLGALACTOSIDEHEAT-LABILE ENTEROTOXIN B-PENTAMER COMPLEXED WITH METANITROPHENYLGALACTOSIDE

Structural highlights 1lt6 is a 10 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ELBP_ECOLX The biological activity of the toxin is produced by the A chain, which activates intracellular adenyl cyclase. Publication Abstract from PubMed BACKGROUND: Escherichia coli heat-labile enterotoxin (LT) is the causative agent of traveller's diarrhoea, and it is also responsible for the deaths of hundreds of thousands of children per year in developing countries. LT is highly homologous in sequence, structure and function to cholera toxin (CT). Both toxins attack intestinal epithelial cells via specific binding to the branched pentasaccharide of ganglioside GM1 at the cell surface. A receptor-binding antagonist which blocked this interaction would potentially constitute a prophylactic drug conferring protection both against the severe effects of cholera itself and against the milder but more common disease caused by LT. RESULTS: Four derivatives of the simple sugar galactose, members of a larger series of receptor antagonists identified by computer modeling and competitive binding studies, have been co-crystallized with either the full LT AB5 holotoxin or the LT B pentamer. These crystal structures have provided detailed views of the toxin in complex with each of the four antagonists: melibionic acid at 2.8 A resolution, lactulose at 2.65 A resolution, metanitrophenylgalactoside (MNPG) at 2.2 A resolution and thiodigalactoside (TDG) at 1.7 A resolution. The binding mode of each galactose derivative was observed 5-15 times, depending on the number of crystallographically independent toxin B pentamers per asymmetric unit. There is a remarkable consistency, with one important exception, in the location and hydrogen-bonding involvement of well-ordered water molecules at the receptor-binding site. CONCLUSIONS: The bound conformations of these receptor antagonist compounds preserve the toxin-galactose interactions previously observed for toxin-sugar complexes, but gain additional favorable interactions. The highest affinity compound, MNPG, is notable in that it displaces a water molecule that is observed to be well-ordered in all other previous and current crystal structures of toxin-sugar complexes. This could be a favorable entropic factor contributing to the increased affinity. The highest affinity members of the present set of antagonists (MNPG and TDG) bury roughly half (400 A2) of the binding-site surface covered by the full receptor GM1 pentasaccharide, despite being considerably smaller. This provides an encouraging basis for the creation of subsequent generations of derived compounds that can compete effectively with the natural receptor. Structural foundation for the design of receptor antagonists targeting Escherichia coli heat-labile enterotoxin.,Merritt EA, Sarfaty S, Feil IK, Hol WG Structure. 1997 Nov 15;5(11):1485-99. PMID:9384564 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 1lt6, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image