Structure of a bacterial multidrug ABC transporter
Structure of a bacterial multidrug ABC transporter
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DOI：
10.1038/nature05155
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发表时间：
2006-09-14
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：
Dawson, Roger J. P.;Locher, Kaspar P.
ABC家族的多药转运蛋白促进多种细胞毒性药物跨细胞膜的输出。这是临床相关的，因为肿瘤细胞可能对化疗中使用的药物产生耐药性。为了了解这个过程的分子基础，我们已经确定了3.0埃的晶体结构的细菌ABC转运蛋白（Sav 1866）从金黄色葡萄球菌。同源二聚体蛋白由12个跨膜螺旋组成，其排列与人多药耐药蛋白MDR 1的交联研究和电子显微镜成像一致，但与细菌脂质翻转酶MsbA的报道截然不同。观察到的，面向外的构象反映了ATP结合状态，两个核苷酸结合结构域紧密接触，两个跨膜结构域形成一个中心腔-推测药物转运途径-这是从脂质双层的内叶和细胞质屏蔽，但暴露于外叶和细胞外空间。
Multidrug transporters of the ABC family facilitate the export of diverse cytotoxic drugs across cell membranes. This is clinically relevant, as tumour cells may become resistant to agents used in chemotherapy. To understand the molecular basis of this process, we have determined the 3.0 angstrom crystal structure of a bacterial ABC transporter (Sav1866) from Staphylococcus aureus. The homodimeric protein consists of 12 transmembrane helices in an arrangement that is consistent with cross-linking studies and electron microscopic imaging of the human multidrug resistance protein MDR1, but critically different from that reported for the bacterial lipid flippase MsbA. The observed, outward-facing conformation reflects the ATP-bound state, with the two nucleotide-binding domains in close contact and the two transmembrane domains forming a central cavity - presumably the drug translocation pathway - that is shielded from the inner leaflet of the lipid bilayer and from the cytoplasm, but exposed to the outer leaflet and the extracellular space.