PfMDR1: mechanisms of transport modulation by functional polymorphisms.
PfMDR1: mechanisms of transport modulation by functional polymorphisms.
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DOI：
10.1371/journal.pone.0023875
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Gil JP
中科院分区：
文献类型：
--
作者：
Ferreira PE;Holmgren G;Veiga MI;Uhlén P;Kaneko A;Gil JP
ATP结合盒（ABC）转运蛋白是一种外排泵，经常与包括疟疾在内的许多生物系统的多药耐药性相关。抗疟药耐药性涉及ABC转运蛋白PfMDR 1，它是人类P-糖蛋白的同源物。二十年的研究表明，pfmdr 1的几个单核苷酸多态性调节体内和/或体外药物敏感性。这些突变影响的潜在生理机制仍不清楚。在这里，我们开发的PfMDR 1在不同的预测构象的结构模型，使转运运动的研究。这种功能多态性的分析允许确定其在运输和抗性中的潜在作用。细菌MsbA ABC泵是PfMDR 1同源物。使用不同构象的MsbA晶体用Modeller软件创建PfMDR 1模型。序列与ClustalW比对，并通过Ali 2D分析，揭示了高水平的二级结构保守性。为了验证潜在的药物结合口袋，我们进行了抗疟对接模拟。使用氨基喹啉作为探针药物在PfMDR 1突变的寄生虫，我们评估的PfMDR 1多态性介导的耐药机制的生理基础。我们集中在PfMDR 1氨基酸残基86，184，1034，1042和1246的众所周知的功能多态性的分析。我们的结构分析表明存在两种不同的生物物理机制PfMDR 1耐药调制。残基86/184/1246中的多态性通过内部变构调节起作用，残基1034和1042在药物袋中直接相互作用。含有突变PfMDR 1变体的寄生虫具有显著改变的氨基喹啉敏感性，其似乎依赖于氨基喹啉疏脂性特征以及PfCRT的空泡外排。我们先前描述了在抗疟药物压力下PfMDR 1多态性的体内选择。现在，连同最近的PfMDR 1功能报告，我们有助于了解这些多态性在寄生虫抗疟药物反应中的特定结构作用。
ATP-Binding Cassette (ABC) transporters are efflux pumps frequently associated with multidrug resistance in many biological systems, including malaria. Antimalarial drug-resistance involves an ABC transporter, PfMDR1, a homologue of P-glycoprotein in humans. Twenty years of research have shown that several single nucleotide polymorphisms in pfmdr1 modulate in vivo and/or in vitro drug susceptibility. The underlying physiological mechanism of the effect of these mutations remains unclear. Here we develop structural models for PfMDR1 in different predicted conformations, enabling the study of transporter motion. Such analysis of functional polymorphisms allows determination of their potential role in transport and resistance. The bacterial MsbA ABC pump is a PfMDR1 homologue. MsbA crystals in different conformations were used to create PfMDR1 models with Modeller software. Sequences were aligned with ClustalW and analysed by Ali2D revealing a high level of secondary structure conservation. To validate a potential drug binding pocket we performed antimalarial docking simulations. Using aminoquinoline as probe drugs in PfMDR1 mutated parasites we evaluated the physiology underlying the mechanisms of resistance mediated by PfMDR1 polymorphisms. We focused on the analysis of well known functional polymorphisms in PfMDR1 amino acid residues 86, 184, 1034, 1042 and 1246. Our structural analysis suggested the existence of two different biophysical mechanisms of PfMDR1 drug resistance modulation. Polymorphisms in residues 86/184/1246 act by internal allosteric modulation and residues 1034 and 1042 interact directly in a drug pocket. Parasites containing mutated PfMDR1 variants had a significant altered aminoquinoline susceptibility that appears to be dependent on the aminoquinoline lipophobicity characteristics as well as vacuolar efflux by PfCRT. We previously described the in vivo selection of PfMDR1 polymorphisms under antimalarial drug pressure. Now, together with recent PfMDR1 functional reports, we contribute to the understanding of the specific structural role of these polymorphisms in parasite antimalarial drug response.
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