title: Structure-based discovery of a pore-binding ligand: towards assembly inhibitors for cholera and related AB5 toxins.
abstract: Cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) are two closely related multi-subunit AB5 proteins responsible for significant morbidity and mortality worldwide. An attractive strategy to prevent disease by these organisms is to interfere with the assembly process of these toxins, since prevention of toxin formation is better than preventing the effects of a toxin which is already formed. The B subunits form a ring with a central pore which surrounds the C-terminal residues of the A subunit. Low molecular mass compounds which would bind in the pore are likely to inhibit proper assembly of the AB5 toxins. In a pharmacophore search based on two side-chains of the A subunit, 3-methylthio-1,4-diphenyl-1H-1, 3,4-triazolium (MDT) was identified as a candidate ligand which might "plug" the pore. A 2.0 A co-crystal structure revealed that a triplet of MDTs indeed bound to the targeted region in two independent LT B pentamers in a remarkably similar manner. Clearly, MDT is a lead for developing assembly antagonists of CT and LT.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, 98195, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Hovey
authors.forename: C L
authors.initials: CL
authors.lastname: Verlinde
authors.forename: E A
authors.initials: EA
authors.lastname: Merritt
authors.forename: W G
authors.initials: WG
authors.lastname: Hol
mesh_terms: D001427:Bacterial Toxins / Q000737:chemistry*; D001665:Binding Sites; D002772:Cholera Toxin / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D004768:Enterotoxins / Q000737:chemistry*; D004926:Escherichia coli / Q000472:pathogenicity; D029968:Escherichia coli Proteins; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011487:Protein Conformation; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*; D014734:Vibrio cholerae / Q000472:pathogenicity
chemical_list: C117743:3-methylthio-1,4-diphenyl-1H-1,3,4-triazolium; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D007473:Ion Channels; D014230:Triazoles; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli