Robinson Mark W, McFerran Neil, Trudgett Alan, Hoey Liz, Fairweather Ian
The School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
J Mol Graph Model. 2004 Dec;23(3):275-84. doi: 10.1016/j.jmgm.2004.08.001.
Although it is well established that benzimidazole (BZMs) compounds exert their therapeutic effects through binding to helminth beta-tubulin and thus disrupting microtubule-based processes in the parasites, the precise location of the benzimidazole-binding site on the beta-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 beta-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 beta-tubulin. However, the atomic structure of the alphabeta-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 beta-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.
尽管苯并咪唑（BZMs）化合物通过与蠕虫β-微管蛋白结合从而破坏寄生虫中基于微管的生理过程来发挥其治疗作用这一点已得到充分证实，但β-微管蛋白分子上苯并咪唑结合位点的确切位置尚未确定。在本研究中，我们利用先前的实验数据作为线索来帮助确定该位点。首先，苯并咪唑抗性与捻转血矛线虫β-微管蛋白同工型-I第200位的苯丙氨酸到酪氨酸的取代有关。其次，利用真菌进行的定点诱变研究表明，该蛋白这一区域的其他残基可影响苯并咪唑与β-微管蛋白的相互作用。然而，αβ-微管蛋白二聚体的原子结构表明，第200位残基和其他相关残基埋藏在蛋白质内部。这就提出了一个问题：苯并咪唑如何与这些明显无法接近的残基相互作用？在本研究中，我们提出了一种机制，通过该机制那些通常被认为与苯并咪唑相互作用的残基可能会变得可被药物接近。此外，通过将阿苯达唑亚砜对接至模拟的捻转血矛线虫β-微管蛋白分子中，我们对赋予线虫苯并咪唑抗性的突变可能如何起作用提供了一种结构解释，同时也为苯并咪唑驱虫药的物种特异性提供了一种可能的解释。
