Energetics and conformational pathways of functional rotation in the multidrug transporter AcrB.
Energetics and conformational pathways of functional rotation in the multidrug transporter AcrB.
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DOI：
10.7554/elife.31715
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发表时间：
2018-03-06
期刊：
影响因子：
7.7
通讯作者：
Kidera A
中科院分区：
文献类型：
--
作者：
Matsunaga Y;Yamane T;Terada T;Moritsugu K;Fujisaki H;Murakami S;Ikeguchi M;Kidera A
多药物转运蛋白AcrB通过质子动力将多种药物转运出细胞。三聚体AcrB的不对称晶体结构表明药物转运的功能旋转机制。尽管从生物化学和模拟研究的这种机制的各种支持形式的证据，功能旋转和质子跨膜易位之间的联系仍然难以捉摸。在这里，计算的最小自由能路径的功能旋转为完整的AcrB三聚体，我们描述的结构和能量的基础背后的功能旋转和质子易位之间的耦合在原子分辨率。自由能计算表明，质子化的Asp408在跨膜部分的药物结合的原聚体驱动的功能旋转。构象途径识别几个跨膜螺旋之间的垂直剪切运动，其调节跨膜中水的交替进入以及在周质中泵送药物的蠕动运动。
The multidrug transporter AcrB transports a broad range of drugs out of the cell by means of the proton-motive force. The asymmetric crystal structure of trimeric AcrB suggests a functionally rotating mechanism for drug transport. Despite various supportive forms of evidence from biochemical and simulation studies for this mechanism, the link between the functional rotation and proton translocation across the membrane remains elusive. Here, calculating the minimum free energy pathway of the functional rotation for the complete AcrB trimer, we describe the structural and energetic basis behind the coupling between the functional rotation and the proton translocation at atomic resolution. Free energy calculations show that protonation of Asp408 in the transmembrane portion of the drug-bound protomer drives the functional rotation. The conformational pathway identifies vertical shear motions among several transmembrane helices, which regulate alternate access of water in the transmembrane as well as peristaltic motions that pump drugs in the periplasm.