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首页> 外文OA文献 >Research data supporting 'Hoechst 33342 Is a Hidden “Janus” amongst Substrates for the Multidrug Efflux Pump LmrP'
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Research data supporting 'Hoechst 33342 Is a Hidden “Janus” amongst Substrates for the Multidrug Efflux Pump LmrP'

机译：支持“ Hoechst 33342是多药外排泵LmrP的底材中的隐藏“剑锋”的研究数据”

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Multidrug transporters mediate the active extrusion of antibiotics and toxic ions from the cell. This reaction is thought to be based on a switch of the transporter between two conformational states, one in which the interior substrate binding cavity is available for substrate binding at the inside of the cell, and another in which the cavity is exposed to the outside of the cell to enable substrate release. Consistent with this model, cysteine cross-linking studies with the Major Facilitator Superfamily drug/proton antiporter LmrP from Lactococcus lactis demonstrated binding of transported benzalkonium to LmrP in its inward-facing state. The fluorescent dye Hoechst 33342 is a substrate for many multidrug transporters and is extruded by efflux pumps in microbial and mammalian cells. Surprisingly, and in contrast to other multidrug transporters, LmrP was found to actively accumulate, rather than extrude, Hoechst 33342 in lactococcal cells. Consistent with this observation, LmrP expression was associated with cellular sensitivity, rather than resistance to Hoechst 33342. Thus, we discovered a hidden "Janus" amongst LmrP substrates that is translocated in reverse direction across the membrane by binding to outward-facing LmrP followed by release from inward-facing LmrP. These findings are in agreement with distance measurements by electron paramagnetic resonance in which Hoechst 33342 binding was found to stabilize LmrP in its outward-facing conformation. Our data have important implications for the use of multidrug exporters in selective targeting of "Hoechst 33342-like" drugs to cells and tissues in which these transporters are expressed. The data are those that were incorporated in the 5 figures of this paper, and are numbered in a similar fashion. The figure legends in the paper explain the meaning of the data.
机译：多药转运蛋白介导细胞中抗生素和有毒离子的主动挤出。该反应被认为是基于转运蛋白在两种构象状态之间的转换，其中一种状态是内部底物结合腔可用于细胞内部的底物结合，而另一种则是该腔暴露于细胞的外部。细胞使底物释放。与该模型一致，半胱氨酸与来自乳酸乳球菌的主要促进剂超家族药物/质子反转运蛋白LmrP的半胱氨酸交联研究表明，运输的苯扎氯铵以其向内的状态与LmrP结合。荧光染料Hoechst 33342是许多多种药物转运蛋白的底物，并通过外排泵挤出到微生物和哺乳动物细胞中。出乎意料的是，与其他多药转运蛋白相比，LmrP被发现在乳球菌细胞中活跃地积累而不是挤出Hoechst 33342。与该观察结果一致，LmrP的表达与细胞敏感性有关，而不是与对Hoechst 33342的抗性有关。因此，我们在LmrP底物中发现了一个隐藏的“ Janus”，该底物通过与向外的LmrP结合并随后与膜结合而沿膜的反方向移位。从面向内的LmrP释放。这些发现与通过电子顺磁共振进行的距离测量一致，在该距离测量中，发现Hoechst 33342结合使LmrP稳定在其向外构象中。我们的数据对于在将“ Hoechst 33342样”药物选择性靶向表达这些转运蛋白的细胞和组织中使用多药出口者具有重要意义。数据是包含在本文的5个图中的数据，并以类似的方式编号。本文中的图例说明了数据的含义。

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