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首页> 外文期刊>Journal of Molecular Biology >Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope.
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Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope.

机译：在HIV-1蛋白酶中优先识别底物的动力学：重新定义底物包膜。

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Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate envelope, because these regions are crucial for drug binding but not for substrate recognition. We extend this model by considering the role of protein dynamics in the interaction of HIV-1 PR with its substrates. We simulated the molecular dynamics of seven PR-substrate complexes to estimate the conformational flexibility of the bound substrates. Interdependence of substrate-protease interactions might compensate for variations in cleavage-site sequences and explain how a diverse set of sequences are recognized as substrates by the same enzyme. This diversity might be essential for regulating sequential processing of substrates. We define a dynamic substrate envelope as a more accurate representation of PR-substrate interactions. This dynamic substrate envelope, described by a probability distribution function, is a powerful tool for drug design efforts targeting ensembles of resistant HIV-1 PR variants with the aim of developing drugs that are less susceptible to resistance.
机译：人类免疫缺陷病毒1型（HIV-1）蛋白酶（PR）可通过加工gag和gag-pro-pol多蛋白来实现病毒成熟。 HIV-1 PR抑制剂（PIs）用于联合抗病毒治疗，但耐药性的出现限制了它们的功效。 HIV-1的快速发展需要在新药设计中考虑耐药性。抗药性HIV-1 PR变体不再有效地被抑制，继续水解天然病毒底物。尽管序列高度不同，但HIV-1 PR底物以保守的三维形状结合，我们称之为底物包膜。早些时候，我们证明了在PI超出底物包膜的地方会产生抗药性突变，因为这些区域对于药物结合而不是底物识别至关重要。我们通过考虑蛋白质动力学在HIV-1 PR及其底物相互作用中的作用来扩展该模型。我们模拟了七个PR-底物复合物的分子动力学，以估计结合底物的构象柔性。底物-蛋白酶相互作用的相互依赖性可能补偿切割位点序列的变化，并解释了如何通过同一酶将多种序列识别为底物。这种多样性对于调节基板的顺序处理可能至关重要。我们将动态基质包膜定义为PR-基质相互作用的更准确表示。这种动态的基质包膜，由概率分布函数描述，是针对靶向耐药性HIV-1 PR变异体的药物设计工作的有力工具，目的是开发对耐药性较不敏感的药物。

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