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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase
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Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase

机译：壬核苷逆转录酶抑制剂的过度感应和通过残留物181突变在HIV-1逆转录酶中的突变

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摘要

Substitutions at residue Y181 in HIV-1 reverse transcriptase (RT), in particular, Y181C, Y181I, and Y181V, are associated with nonnucleoside RT inhibitor (NNRTI) cross-resistance. In this study, we used kinetic and thermodynamic approaches, in addition to molecular modeling, to gain insight into the mechanisms by which these substitutions confer resistance to nevirapine (NVP), efavirenz (EFV), and rilpivirine (RPV). Using pre-steady-state kinetics, we found that the dissociation constant (K-d) values for inhibitor binding to the Y181C and Y181I RT-template/primer (T/P) complexes were significantly reduced. In the presence of saturating concentrations of inhibitor, the Y181C RT-T/P complex incorporated the next correct deoxynucleoside triphosphate (dNTP) more efficiently than the wild-type (WT) complex, and this phenotype correlated with decreased mobility of the RT on the T/P substrate. Interestingly, we found that the Y181F substitution in RT-which represents a transitional mutation between Y181 and Y181I/V, or a partial revertant-conferred hypersusceptibility to EFV and RPV at both the virus and enzyme levels. EFV and RPV bound more tightly to Y181F RT-T/P. Furthermore, inhibitor-bound Y181F RT-T/P was less efficient than the WT complex in incorporating the next correct dNTP, and this could be attributed to increased mobility of Y181F RT on the T/P substrate. Collectively, our data highlight the key role that Y181 in RT plays in NNRTI binding.
机译：在HIV-1逆转录酶（RT）中残留Y181的取代，特别是Y181C，Y181I和Y181V与非核苷RT抑制剂（NNRTI）交叉抗性相关。在这项研究中，除了分子建模之外，我们使用动力学和热力学方法，以了解这些取代赋予Nevirapine（NVP），EFAVIRENZ（EFV）和瑞培（RPV）的机制的洞察力。使用预稳态动力学，发现抑制剂与Y181C和Y181I RT-TAME /底漆（T / P）复合物的抑制剂结合的解离常数（K-D）值显着降低。在存在饱和浓度的抑制剂的存在下，Y181C RT-T / P复合物在野生型（WT）复合物中更有效地掺入了下一个正确的脱氧核苷三磷酸（DNTP），并且这种表型与RT的下降率降低相关T / P衬底。有趣的是，我们发现RT-I181F取代代表Y181和Y181I / V之间的过渡突变，或在病毒和酶水平的EFV和RPV之间的部分倒剂赋予的过度感应。 EFV和RPV更紧密地绑定到Y181F RT-T / p。此外，抑制剂结合的Y181F RT-T / P比结合下一个正确的DNTP在WT复合物中的效率较低，并且这可能归因于在T / P衬底上的Y181F Rt的迁移率增加。统称，我们的数据突出了NNRTI绑定中的RT参与的关键作用。

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