Structure of an ABC transporter in complex with its binding protein
Structure of an ABC transporter in complex with its binding protein
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DOI：
10.1038/nature05626
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发表时间：
2007-03-08
期刊：
影响因子：
64.8
通讯作者：
Locher, Kaspar P.
中科院分区：
文献类型：
--
作者：
Hollenstein, Kaspar;Frei, Dominik C.;Locher, Kaspar P.
ATP结合盒（ABC）转运蛋白蛋白遍布细胞膜（1）。尽管临床相关的ABC出口商与各种疾病有关或引起癌细胞的多药耐药性（2,3），但细菌ABC进口商对于摄取营养素至关重要（4），包括罕见的元素，例如钼。对其机制的详细理解需要在高分辨率和不同构象中直接可视化。我们最近的多饮用ABC出口商SAV1866的结构揭示了跨膜结构域的向外构象与核苷酸结合结构域的封闭构象结合，反映了ATP结合的状态（5）。在这里，我们介绍了从Archaeoglobus fulgidus及其结合蛋白（MODA）中提取的假定钼酸酯转运蛋白（MODB（2）C（2））的3.1埃脉冲晶体结构。 MODB亚基的十二个跨膜螺旋提供了一个向内的构象，在外膜边界附近有一个封闭的门。 ATP-Hydrolysing ModC亚基揭示了无核苷酸的开放构象，而附着的结合蛋白将底物结合裂缝与推定的易位途径的入口保持一致。 MODB（2）C（2）A与SAV1866的结构比较表明一种常见的交替访问和释放机制，ATP的结合促进了向外的构象和水解产物的解离，从而促进了面向内向的构象。
ATP-binding cassette (ABC) transporter proteins carry diverse substrates across cell membranes(1). Whereas clinically relevant ABC exporters are implicated in various diseases or cause multidrug resistance of cancer cells(2,3), bacterial ABC importers are essential for the uptake of nutrients(4), including rare elements such as molybdenum. A detailed understanding of their mechanisms requires direct visualization at high resolution and in distinct conformations. Our recent structure of the multidrug ABC exporter Sav1866 has revealed an outward-facing conformation of the transmembrane domains coupled to a closed conformation of the nucleotide-binding domains, reflecting the ATP-bound state(5). Here we present the 3.1 angstrom crystal structure of a putative molybdate transporter (ModB(2)C(2)) from Archaeoglobus fulgidus in complex with its binding protein ( ModA). Twelve transmembrane helices of the ModB subunits provide an inward-facing conformation, with a closed gate near the external membrane boundary. The ATP-hydrolysing ModC subunits reveal a nucleotide-free, open conformation, whereas the attached binding protein aligns the substrate-binding cleft with the entrance to the presumed translocation pathway. Structural comparison of ModB(2)C(2)A with Sav1866 suggests a common alternating access and release mechanism, with binding of ATP promoting an outward-facing conformation and dissociation of the hydrolysis products promoting an inward-facing conformation.