Structural basis of RND-type multidrug exporters.
Structural basis of RND-type multidrug exporters.
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DOI：
10.3389/fmicb.2015.00327
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发表时间：
2015
影响因子：
5.2
通讯作者：
Sakurai K
中科院分区：
文献类型：
--
作者：
Yamaguchi A;Nakashima R;Sakurai K
细菌多药输出体是细胞内固有的膜转运体，起着细胞自我防御机制的作用。多药出口商最显著的特点是出口范围广泛的毒品和有毒化合物。这些出口蛋白的过度表达会导致多药耐药。耐多药病原菌已经成为现代化疗中的一个严重问题。在过去的十年里，对细菌多药输出体结构的研究揭示了多药识别和输出机制。在这篇综述中，我们主要讨论RND类型的多药输出子，特别是AcrAB-TolC，革兰氏阴性菌中的主要药物输出子。RND类药物输出体是由细胞膜转运体、外膜通道和接头蛋白组成的三元复合体。细胞膜转运蛋白和外膜通道是同源三聚体，然而，对于这三部分复合体中接头蛋白的数量还没有达成共识。细胞膜转运蛋白的三种单体在运输过程中具有不同的构象(进入、结合和挤出)。药物在这三种单体发生有序构象变化后，通过功能旋转机制与离子对中的质子接力循环相结合，由质子转移驱动。多药识别是基于多部位药物结合机制的，在该机制中，细胞膜出口体中的两个巨大的多药物结合口袋识别广泛的底物，这是底物分子部分结构所特有的众多结合位点排列的结果。庞大的多药物结合口袋即使对于单个底物也可能有许多结合部位，这表明底物在运输过程中可能会在结合部位之间移动，这一想法被称为多部位药物振荡假说。这一假说与细胞膜出口蛋白广泛的底物专一性以及它们高效地将药物从细胞中排出是一致的。底物通过底物转运通道的蠕动运动，通过两个多药结合袋进行运输。尽管临床上还没有细菌多药出口商的抑制剂，但根据结构信息开发抑制剂的努力正在进行中。
Bacterial multidrug exporters are intrinsic membrane transporters that act as cellular self-defense mechanism. The most notable characteristics of multidrug exporters is that they export a wide range of drugs and toxic compounds. The overexpression of these exporters causes multidrug resistance. Multidrug-resistant pathogens have become a serious problem in modern chemotherapy. Over the past decade, investigations into the structure of bacterial multidrug exporters have revealed the multidrug recognition and export mechanisms. In this review, we primarily discuss RND-type multidrug exporters particularly AcrAB-TolC, major drug exporter in Gram-negative bacteria. RND-type drug exporters are tripartite complexes comprising a cell membrane transporter, an outer membrane channel and an adaptor protein. Cell membrane transporters and outer membrane channels are homo-trimers; however, there is no consensus on the number of adaptor proteins in these tripartite complexes. The three monomers of a cell membrane transporter have varying conformations (access, binding, and extrusion) during transport. Drugs are exported following an ordered conformational change in these three monomers, through a functional rotation mechanism coupled with the proton relay cycle in ion pairs, which is driven by proton translocation. Multidrug recognition is based on a multisite drug-binding mechanism, in which two voluminous multidrug-binding pockets in cell membrane exporters recognize a wide range of substrates as a result of permutations at numerous binding sites that are specific for the partial structures of substrate molecules. The voluminous multidrug-binding pocket may have numerous binding sites even for a single substrate, suggesting that substrates may move between binding sites during transport, an idea named as multisite-drug-oscillation hypothesis. This hypothesis is consistent with the apparently broad substrate specificity of cell membrane exporters and their highly efficient ejection of drugs from the cell. Substrates are transported through dual multidrug-binding pockets via the peristaltic motion of the substrate translocation channel. Although there are no clinically available inhibitors of bacterial multidrug exporters, efforts to develop inhibitors based on structural information are underway.
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影响因子：
3.2
作者：
Kobayashi, N;Nishino, K;Yamaguchi, A
通讯作者：
Yamaguchi, A
影响因子：
16
作者：
Bavro, Vassiliy N.;Pietras, Zbigniew;Furnham, Nicholas;Perez-Cano, Laura;Fernandez-Recio, Juan;Pei, Xue Yuan;Misra, Rajeev;Luisi, Ben
通讯作者：
Luisi, Ben
影响因子：
64.8
作者：
Dawson, Roger J. P.;Locher, Kaspar P.
通讯作者：
Locher, Kaspar P.
影响因子：
7.7
作者：
Eicher, Thomas;Seeger, Markus A.;Pos, Klaas M.
通讯作者：
Pos, Klaas M.
影响因子：
2.9
作者：
Ferrandez, Yann;Monlezun, Laura;Broutin, Isabelle
通讯作者：
Broutin, Isabelle