Structure-based discovery of a pore-binding ligand: towards assembly inhibitors for cholera and related AB5 toxins.
J Mol Biol
; 285(3): 1169-78, 1999 Jan 22.
Article
en En
| MEDLINE
| ID: mdl-9887271
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Toxinas Bacterianas
/
Triazoles
/
Toxina del Cólera
/
Proteínas de Escherichia coli
/
Enterotoxinas
/
Canales Iónicos
Idioma:
En
Revista:
J Mol Biol
Año:
1999
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Países Bajos