Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope.
Dynamics of preferential substrate recognition in HIV-1 protease: redefining the substrate envelope.
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DOI：
10.1016/j.jmb.2011.03.053
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发表时间：
2011-07-22
影响因子：
5.6
通讯作者：
Schiffer CA
中科院分区：
文献类型：
--
作者：
Ozen A;Haliloğlu T;Schiffer CA
HIV-1蛋白酶(PR)通过处理Gag和Gag-Pro-Pol多蛋白使病毒成熟。尽管HIV-1 PR抑制剂(PI)被用于联合抗病毒治疗，但耐药性的出现限制了它们的疗效。HIV-1的快速演变要求在新的药物设计策略中考虑耐药性。耐药的HIV-1PR变种虽然不再有效地被抑制，但继续有效地水解天然的病毒底物。尽管HIV-1PR底物在序列上高度多样化，但它以一种保守的三维形状结合，我们将其定义为“底物包膜”。我们之前已经证明，当PI突出到底物包膜之外时，就会出现耐药性突变，因为这些区域对药物结合至关重要，但对底物识别不是。在这里，我们通过考虑蛋白质动力学在HIV-1 PR与其底物相互作用中的作用来扩展这个模型。对PR-底物络合物进行了7个分子动力学模拟，以估算其络合物中底物的构象柔性。底物-蛋白酶相互作用的相互依赖性可以补偿裂解位点序列的变化，并解释了同一酶如何将一组不同的序列识别为底物。这种多样性对于调节底物的顺序加工可能是必不可少的。我们还将动态底物包络定义为PR-底物相互作用的更准确表示。这种由概率分布函数描述的动态底物包膜是针对耐药HIV-1 PR变种集合的药物设计工作的强大工具，目的是开发不太容易耐药的药物。
HIV-1 protease (PR) permits viral maturation by processing the Gag and Gag-Pro-Pol polyproteins. Though HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy, the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates the consideration of drug resistance in novel drug-design strategies. Drug-resistant HIV-1 PR variants, while no longer efficiently inhibited, continue to efficiently hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we defined as the “substrate envelope”. We previously showed that resistance mutations arise where PIs protrude beyond the substrate envelope, as these regions are crucial for drug binding but not for substrate recognition. Here, we extend this model by considering the role of protein dynamics in the interaction of HIV-1 PR with its substrates. Seven molecular dynamics simulations of PR-substrate complexes were performed to estimate the conformational flexibility of substrates in their complexes. Interdependency of the substrate-protease interactions may compensate for the variations in cleavage-site sequences, and explain how a diverse set of sequences can be recognized as substrates by the same enzyme. This diversity may be essential for regulating sequential processing of substrates. We also 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.
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