Gerlach J H, Endicott J A, Juranka P F, Henderson G, Sarangi F, Deuchars K L, Ling V
Nature. 1986;324(6096):485-9. doi: 10.1038/324485a0.
Increased expression of P-glycoprotein, a plasma membrane glycoprotein of relative molecular mass (Mr) 170,000 (170K), occurs in a wide variety of cell lines that exhibit pleiotropic resistance to unrelated drugs. The presence of P-glycoprotein in human cancers refractory to chemotherapy suggests that tumour cells with multidrug resistance can arise during malignant progression. We have discovered striking homology between P-glycoprotein and the HlyB protein, a 66K Escherichia coli membrane protein required for the export of haemolysin (protein of Mr 107K). P-glycoprotein can be viewed as a tandem duplication of the HlyB protein. The hydropathy profiles of the two proteins are similar and reveal an extensive transmembrane region resembling those found in pore-forming plasma membrane proteins. The C-terminal region of P-glycoprotein and the HlyB protein contain sequences homologous to the nucleotide-binding domains of a group of closely related bacterial ATP-binding proteins. We propose a model for multidrug resistance in which P-glycoprotein functions as an energy-dependent export pump to reduce intracellular levels of anticancer drugs.
P-糖蛋白是一种相对分子质量（Mr）为170,000（170K）的质膜糖蛋白，在多种对无关药物表现出多药耐药性的细胞系中表达增加。P-糖蛋白在对化疗难治的人类癌症中的存在表明，具有多药耐药性的肿瘤细胞可能在恶性进展过程中出现。我们发现P-糖蛋白与HlyB蛋白之间存在显著同源性，HlyB蛋白是一种66K的大肠杆菌膜蛋白，是溶血素（Mr 107K的蛋白）分泌所必需的。P-糖蛋白可被视为HlyB蛋白的串联重复。这两种蛋白的亲水性图谱相似，显示出一个广泛的跨膜区域，类似于在形成孔道的质膜蛋白中发现的区域。P-糖蛋白和HlyB蛋白的C末端区域包含与一组密切相关的细菌ATP结合蛋白的核苷酸结合域同源的序列。我们提出了一种多药耐药模型，其中P-糖蛋白作为一种能量依赖性输出泵，以降低细胞内抗癌药物的水平。
