A possible model of benzimidazole binding to beta-tubulin disclosed by invoking an inter-domain movement

Publication Type:
Journal Article
Journal of Molecular Graphics and Modelling, 2004, 23 (3), pp. 275 - 284
Issue Date:
Full metadata record
Files in This Item:
Filename Description Size
Thumbnail2009005083OK.pdf585.69 kB
Adobe PDF
Although it is well established that benzimidazole (BZMs) compounds exert their therapeutic effects through binding to helminth ? tubulin and thus disrupting microtubule-based processes in the parasites, the precise location of the benzimidazole-binding site on the ?-tubulin molecule has yet to be determined. In the present study, we have used previous experimental data as cues to help identify this site. Firstly, benzimidazole resistance has been correlated with a phenylalanine-to-tyrosine substitution at position 200 of Haemonchus contortus ?-tubulin isotype-I. Secondly, site-directed mutagenesis studies, using fungi, have shown that other residues in this region of the protein can influence the interaction of benzimidazoles with ?-tubulin. However, the atomic structure of the ??-tubulin dimer shows that residue 200 and the other implicated residues are buried within the protein. This poses the question: how might benzimidazoles interact with these apparently inaccessible residues? In the present study, we present a mechanism by which those residues generally believed to interact with benzimidazoles may become accessible to the drugs. Furthermore, by docking albendazole-sulphoxide into a modelled H. contortus ?-tubulin molecule we offer a structural explanation for how the mutation conferring benzimidazole resistance in nematodes may act, as well as a possible explanation for the species-specificity of benzimidazole anthelmintics.
Please use this identifier to cite or link to this item: