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首页> 外文期刊>Biochemistry >Interaction of the indole class of vacuolar H+-ATPase inhibitors with lipid bilayers
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Interaction of the indole class of vacuolar H+-ATPase inhibitors with lipid bilayers

机译：吲哚类液泡H + -ATPase抑制剂与脂质双层的相互作用

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摘要

The selective inhibitor of osteoclastic V-ATPase (2Z,4E)-5-(5,6-dichloro-2-indolyi)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB 242784), member of the indole class of V-ATPase inhibitors, is expected to target the membrane-bound domain of the enzyme. A structural study of the interaction of this inhibitor with the lipidic environment is an essential step in the understanding of the mechanism of inhibition. In this work, a comprehensive study of the relevant features of this interaction was performed. Inhibitor partition coefficients to lipid vesicles as well as its transverse location, orientation (order parameters), and dynamics while bound to bilayers were determined through photophysical techniques, taking advantage of the intrinsic fluorescence of the molecule. To better evaluate the functionally relevant features of SB 242784, a second inhibitor, INH-1, from the same class and having a reduced activity was also examined. It is shown that regarding membrane interaction their properties remain very similar for both molecules, suggesting that the differences in inhibition efficiencies are solely a consequence of the molecular recognition processes within the inhibition site in the V-ATPase.
机译：破骨细胞V-ATPase（2Z，4E）-5-（5,6-二氯-2-吲哚基）-2-甲氧基-N-（1,2,2,6,6-五甲基哌啶-4-基的选择性抑制剂）-2,4-戊二烯酰胺（SB 242784）是V-ATPase抑制剂的吲哚类成员，预计可靶向该酶的膜结合结构域。对该抑制剂与脂质环境相互作用的结构研究是理解抑制机理必不可少的步骤。在这项工作中，对这种相互作用的相关特征进行了全面的研究。利用分子的固有荧光，通过光物理技术确定与双层结合时抑制剂在脂质囊泡中的分配系数及其横向位置，方向（有序参数）和动力学。为了更好地评估SB 242784的功能相关特征，还研究了另一种同种且活性降低的抑制剂INH-1。结果表明，关于膜相互作用，它们的性质对于两个分子仍然非常相似，这表明抑制效率的差异仅是V-ATPase抑制位点内分子识别过程的结果。

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