Jones P M, George A M
Department of Cell and Molecular Biology, University of Technology Sydney, Sydney, NSW 2007, Australia.
J Membr Biol. 1998 Nov 15;166(2):133-47. doi: 10.1007/s002329900455.
Multidrug resistance to anti-cancer drugs is a major medical problem. Resistance is manifested largely by the product of the human MDR1 gene, P-glycoprotein, an ABC transporter that is an integral membrane protein of 1280 amino acids arranged into two homologous halves, each comprising 6 putative transmembrane alpha-helices and an ATP binding domain. Despite the plethora of data from site-directed, scanning and domain replacement mutagenesis, epitope mapping and photoaffinity labeling, a clear structural model for P-glycoprotein remains largely elusive. In this report, we propose a new model for P-glycoprotein that is supported by the vast body of previous data. The model comprises 2 membrane-embedded 16-strand beta-barrels, attached by short loops to two 6-helix bundles beneath each barrel. Each ATP binding domain contributes 2 beta-strands and 1 alpha-helix to the structure. This model, together with an analysis of the amino acid sequence alignment of P-glycoprotein isoforms, is used to delineate drug binding and translocation sites. We show that the locations of these sites are consistent with mutational, kinetic and labeling data.
抗癌药物的多药耐药性是一个主要的医学问题。耐药性在很大程度上由人类MDR1基因的产物P-糖蛋白表现出来，P-糖蛋白是一种ABC转运蛋白，是一种由1280个氨基酸组成的整合膜蛋白，排列成两个同源部分，每个部分包含6个假定的跨膜α-螺旋和一个ATP结合结构域。尽管有大量来自定点、扫描和结构域置换诱变、表位作图和光亲和标记的数据，但P-糖蛋白的清晰结构模型在很大程度上仍然难以捉摸。在本报告中，我们提出了一个由大量先前数据支持的P-糖蛋白新模型。该模型由2个嵌入膜的16链β-桶组成，通过短环连接到每个桶下方的两个6螺旋束。每个ATP结合结构域为该结构贡献2条β-链和1个α-螺旋。该模型，连同对P-糖蛋白异构体氨基酸序列比对的分析，用于描绘药物结合和转运位点。我们表明，这些位点的位置与突变、动力学和标记数据一致。
