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Retroviral proteases: correlating substrate recognition with both selected and native inhibitor resistance

机译:逆转录病毒蛋白酶:将底物识别与选定的和天然的抑制剂抗性相关

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A diverse group of retroviral proteases were analyzed to correlate mechanisms of substrate recognition with resistance to HIV-1 protease active-site inhibitors. Here it was shown that HIV-1 protease utilized a pathway common to many retroviral proteases, for recognition of mutated Gag/Pol cleavage sites, in order to become resistant to active-site inhibitors. While HIV-1 and HIV-2 resulted from independent cross-species transmissions of simian immunodeficiency virus into humans, HIV-2 has native primary resistance to many HIV-1 protease inhibitors as do many other retroviral proteases. The native multi-drug resistance of those proteases contributed to the lack of treatments for the respective life-long infections. Analysis of interactions between retroviral proteases and Gag/Pol substrates revealed that protease interactions weighted towards cleavage site residues P4-P4' resulted in inhibitor sensitivity, while interactions weighted towards residues P12-P5/P5'-P12' gave inhibitor resistance. In addition, a mechanism was identified for human T-cell leukemia virus type-1 protease that allowed re-weighting of the protease interactions with substrate residues P4-P4' and P12-P5/P5'-P12' using anti-parallel beta-sheets that connected the protease flaps to the substrate-grooves. Those anti-parallel beta-sheets are common to all studied retroviral proteases. The critical role of the retroviral protease substrate-grooves in substrate recognition and inhibitor resistance makes them a potential target.
机译:分析了多种逆转录病毒蛋白酶,以将底物识别机制与对HIV-1蛋白酶活性位点抑制剂的抗性相关。此处显示,HIV-1蛋白酶利用了许多逆转录病毒蛋白酶共有的途径来识别突变的Gag / Pol切割位点,从而对活性位点抑制剂产生抗性。尽管HIV-1和HIV-2是由猿猴免疫缺陷病毒向人类的独立跨物种传播所致,但HIV-2与许多其他逆转录病毒蛋白酶一样,对许多HIV-1蛋白酶抑制剂具有天然的主要耐药性。这些蛋白酶的天然多药耐药性导致缺乏针对各个终生感染的治疗方法。逆转录病毒蛋白酶与Gag / Pol底物之间相互作用的分析表明,蛋白酶的相互作用偏重于裂解位点残基P4-P4'导致了抑制剂的敏感性,而相互作用的残基偏重于P12-P5 / P5'-P12'产生了抑制剂抗性。此外,还确定了一种人类T细胞白血病病毒1型蛋白酶的机制,该机制可使用反平行β-重链技术重新评估蛋白酶与底物残基P4-P4'和P12-P5 / P5'-P12'的相互作用。将蛋白酶皮瓣连接到底物凹槽的薄片。这些反平行β-折叠是所有研究的逆转录病毒蛋白酶共有的。逆转录病毒蛋白酶底物槽在底物识别和抑制剂抗性中的关键作用使其成为潜在的靶标。

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