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

Robinson, MW; McFerran, N; Trudgett, A; Hoey, L; Fairweather, I

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

Robinson, MW

McFerran, N Trudgett, A Hoey, L Fairweather, I

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Publication Type:: Journal Article
Citation:: Journal of Molecular Graphics and Modelling, 2004, 23 (3), pp. 275 - 284
Issue Date:: 2004-12-01

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Field	Value	Language
dc.contributor.author	Robinson, MW https://orcid.org/0000-0001-7191-0034	en_US
dc.contributor.author	McFerran, N	en_US
dc.contributor.author	Trudgett, A	en_US
dc.contributor.author	Hoey, L	en_US
dc.contributor.author	Fairweather, I	en_US
dc.date.available	2004-08-31	en_US
dc.date.issued	2004-12-01	en_US
dc.identifier.citation	Journal of Molecular Graphics and Modelling, 2004, 23 (3), pp. 275 - 284	en_US
dc.identifier.issn	1093-3263	en_US
dc.identifier.uri	http://hdl.handle.net/10453/8497
dc.description.abstract	Although it is well established that benzimidazole (BZMs) compounds exert their therapeutic effects through binding to helminth β-tubulin and thus disrupting microtubule-based processes in the parasites, the precise location of the benzimidazole-binding site on the β-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 β-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 β-tubulin. However, the atomic structure of the αβ-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 β-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. © 2004 Elsevier Inc. All rights reserved.	en_US
dc.relation.ispartof	Journal of Molecular Graphics and Modelling	en_US
dc.relation.isbasedon	10.1016/j.jmgm.2004.08.001	en_US
dc.subject.classification	Biophysics	en_US
dc.subject.classification	Medicinal & Biomolecular Chemistry	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Haemonchus	en_US
dc.subject.mesh	Fasciola hepatica	en_US
dc.subject.mesh	Albendazole	en_US
dc.subject.mesh	Benzimidazoles	en_US
dc.subject.mesh	Tubulin	en_US
dc.subject.mesh	Helminth Proteins	en_US
dc.subject.mesh	Anthelmintics	en_US
dc.subject.mesh	Binding Sites	en_US
dc.subject.mesh	Amino Acid Sequence	en_US
dc.subject.mesh	Protein Structure, Tertiary	en_US
dc.subject.mesh	Drug Resistance	en_US
dc.subject.mesh	Mutation	en_US
dc.subject.mesh	Models, Chemical	en_US
dc.subject.mesh	Molecular Sequence Data	en_US
dc.title	A possible model of benzimidazole binding to β-tubulin disclosed by invoking an inter-domain movement	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	23	en_US
utslib.for	0307 Theoretical and Computational Chemistry	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	0803 Computer Software	en_US
dc.location.activity	United States
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	closed_access
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	23	en_US

Abstract:

Although it is well established that benzimidazole (BZMs) compounds exert their therapeutic effects through binding to helminth β-tubulin and thus disrupting microtubule-based processes in the parasites, the precise location of the benzimidazole-binding site on the β-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 β-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 β-tubulin. However, the atomic structure of the αβ-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 β-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. © 2004 Elsevier Inc. All rights reserved.

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http://hdl.handle.net/10453/8497