Inward- and outward-facing X-ray crystal structures of homodimeric P-glycoprotein CmABCB1
Inward- and outward-facing X-ray crystal structures of homodimeric P-glycoprotein CmABCB1
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DOI：
10.1038/s41467-018-08007-x
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发表时间：
2019-01-08
影响因子：
16.6
通讯作者：
Kato, Hiroaki
中科院分区：
文献类型：
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作者：
Kodan, Atsushi;Yamaguchi, Tomohiro;Kato, Hiroaki
P-糖蛋白从细胞中挤出大量异生物质，从而保护组织免受其毒性作用。单向多药泵的机械基础仍然未知，主要是由于缺乏高分辨率的结构信息的分子的交替构象状态。在这里，我们报告了一对同源二聚体的P-糖蛋白的结构：一个面向外的构象状态与绑定的核苷酸和面向内的载脂蛋白状态，在1.9埃和3.0埃的分辨率，分别。在这种高分辨率下可以清楚地观察到的特征包括与Mg 2+的八面体配位的ATP结合;在跨膜螺旋（TM）1、3和6之间的紧密连接的帮助下体积显著变化的内室;稳定外向构象的谷氨酸-精氨酸相互作用;以及TM 1和TM 3之间的广泛相互作用，这是将多药物转运蛋白与floppases区分开的特性。这些结构元素被认为参与了转运蛋白的机制。
P-glycoprotein extrudes a large variety of xenobiotics from the cell, thereby protecting tissues from their toxic effects. The machinery underlying unidirectional multidrug pumping remains unknown, largely due to the lack of high-resolution structural information regarding the alternate conformational states of the molecule. Here we report a pair of structures of homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide and an inward-facing apo state, at resolutions of 1.9 angstrom and 3.0 angstrom, respectively. Features that can be clearly visualized at this high resolution include ATP binding with octahedral coordination of Mg2+; an inner chamber that significantly changes in volume with the aid of tight connections among transmembrane helices (TM) 1, 3, and 6; a glutamate-arginine interaction that stabilizes the outward-facing conformation; and extensive interactions between TM1 and TM3, a property that distinguishes multidrug transporters from floppases. These structural elements are proposed to participate in the mechanism of the transporter.