近日,来自普渡大学、霍华德休斯医学研究所的研究人员报道了来自秀丽隐杆线虫的多药蛋白P-糖蛋白(P-gp)的晶体结构。

-2012年10月25日《自然》


中文翻译


【题目】秀丽隐杆线虫中多药运载体P糖蛋白的晶体结构

【译文】 P糖蛋白(P-gp)是一种ATP结合基因盒运载体,它赋予癌症细胞多药耐受性。它还影响癌症不相关药物和外源性化学药物的吸收、分布和清除。基于这些原因,P-gp的结构和功能在过去数十年被广泛研究。本研究报道了秀丽隐杆线虫中P-gp的生化特征和分辨率为3.4 Å的晶体结构。我们发现P-gp在双层膜中对抗癌药物放线菌素D和紫杉醇的显著亲和力比去垢剂分别高了4000和100倍。当药物在膜中进入运载体时,这种亲和增强作用突出了膜分配的重要性。而且,晶体结构中运载体在膜内叶水平打开了其药物通道。在膜开口的侧面螺旋中,我们观察到延长的环,这些杂环可能介导药物结合,发挥铰链的作用以控制通路。我们还发现了跨膜和偶联了ATP水解作用以发挥转运作用的核苷酸结合结构域之间的界面含有一个球窝接头和盐桥,类似于ATP结合基因盒输入载体,表明ATP结合基因盒输出载体和输入体可能利用类似机制,以获得运输的交替通道。最后,来源于秀丽隐杆线虫的P-gp结构的人类P-gp模型不仅仅与数十年的生化分析一致,还有助于解释关于Phe335Ala突变体复杂的功能数据。这些结构增加了我们对这种重要分子功能和结构的理解。 

英文原稿


[Title]: Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans

[Authors]:Mi Sun Jin,1 Michael L. Oldham,2 Qiuju Zhang2 & Jue Chen1, 2

[Abstract]P-glycoprotein (P-gp) is an ATP-binding cassette transporter that confers multidrug resistance in cancer cells. It also affects the absorption, distribution and clearance of cancer-unrelated drugs and xenobiotics. For these reasons, the structure and function of P-gp have been studied extensively for decades. Here we present biochemical characterization of P-gp from Caenorhabditis elegans and its crystal structure at a resolution of 3.4 ångströms. We find that the apparent affinities of P-gp for anticancer drugs actinomycin D and paclitaxel are approximately 4,000 and 100 times higher, respectively, in the membrane bilayer than in detergent. This affinity enhancement highlights the importance of membrane partitioning when a drug accesses the transporter in the membrane. Furthermore, the transporter in the crystal structure opens its drug pathway at the level of the membrane’s inner leaflet. In the helices flanking the opening to the membrane, we observe extended loops that may mediate drug binding, function as hinges to gate the pathway or both. We also find that the interface between the transmembrane and nucleotide-binding domains, which couples ATP hydrolysis to transport, contains a ball-and-socket joint and salt bridges similar to the ATP-binding cassette importers, suggesting that ATP-binding cassette exporters and importers may use similar mechanisms to achieve alternating access for transport. Finally, a model of human P-gp derived from the structure of C. elegans P-gp not only is compatible with decades of biochemical analysis, but also helps to explain perplexing functional data regarding the Phe335Ala mutant. These results increase our understanding of the structure and function of this important molecule.

原文地址

http://www.nature.com/nature/journal/v490/n7421/full/nature11448.html

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