Murakami Satoshi
Department of Life Science, Tokyo Institute of Technology, Nagatsuta, Yokohama, Japan.
Curr Opin Struct Biol. 2008 Aug;18(4):459-65. doi: 10.1016/j.sbi.2008.06.007. Epub 2008 Aug 9.
Resistance nodulation cell division (RND) transporters are one of the main causes of the bacterial multidrug resistance. They pump a wide range of antibiotics out of the cell by proton motive force. AcrB is the major RND transporter in Escherichia coli. Recently, the crystal structures of AcrB have been determined by different space groups. All these structures are consistent with asymmetric trimer. Each monomer has different conformation corresponding to one of the three functional states of the transport cycle. Transporting hydrophobic drug was bound in the periplasmic domain on one of the three monomers. The transport pathway with alternating access mechanism is located at the hydrophilic domain protruded into the periplasmic space while this mechanism of other transporter families like ATP binding cassette (ABC) and major facilitator superfamily (MFS) transporter is located in the membrane-embedded region. For the RND, protonation might also take place asymmetrically at the functionally important charged residues in the transmembrane (TM) region. The structures indicate that drugs are transported by a three-step functional rotation in which substrates undergo ordered binding change.
耐药-结瘤-细胞分裂（RND）转运蛋白是细菌多药耐药的主要原因之一。它们利用质子动力将多种抗生素泵出细胞。AcrB是大肠杆菌中的主要RND转运蛋白。最近，已通过不同的空间群确定了AcrB的晶体结构。所有这些结构都与不对称三聚体一致。每个单体具有与转运循环的三种功能状态之一相对应的不同构象。疏水性药物在三个单体之一的周质结构域中结合。具有交替 access 机制的转运途径位于突出到周质空间的亲水性结构域，而其他转运蛋白家族如ATP结合盒（ABC）和主要促进剂超家族（MFS）转运蛋白的这种机制位于膜嵌入区域。对于RND，质子化也可能在跨膜（TM）区域中功能重要的带电荷残基处不对称发生。这些结构表明药物通过三步功能旋转进行转运，其中底物经历有序的结合变化。
