Effects of efavirenz binding on the subunit equilibria of HIV-1 reverse transcriptase
Effects of efavirenz binding on the subunit equilibria of HIV-1 reverse transcriptase
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DOI：
10.1021/bi051915z
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发表时间：
2006-03-07
期刊：
影响因子：
2.9
通讯作者：
Barkley, MD
中科院分区：
文献类型：
--
作者：
Venezia, CF;Howard, KJ;Barkley, MD
最近的研究表明，非核苷逆转录酶抑制剂 (NNRTI) 对 HIV-1 逆转录酶 (RT) 的 p66 和 p51 亚基的二聚化具有不同的影响。依非韦伦是目前用于高活性抗逆转录病毒治疗的三种 NNRTI 之一，可增强亚基二聚化。每个亚基和两个亚基的等摩尔混合物的沉降平衡实验用于测量在不存在和存在药物饱和浓度的情况下RT的三个偶联二聚反应的解离常数。在依非韦伦结合后，p51/p51 同二聚体、p66/p66 同二聚体和 p66/p51 异二聚体的二聚常数分别增加 600、50 和 25 倍。 NNRTI 对 RT 二聚化的影响与亚基结合/解离和抑制剂结合之间的热力学联系一致。对 p66/p51 异二聚体晶体结构的分析表明，依非韦伦结合会在二聚体界面引起微小的结构变化。
Recent studies showed that nonnucleoside reverse transcriptase inhibitors (NNRTIs) have variable effects on dimerization of p66 and p51 subunits of HIV-1 reverse transcriptase (RT). Efavirenz, one of three NNRTIs currently used in highly active anti-retroviral therapy, enhances subunit dimerization. Sedimentation equilibrium experiments on each subunit and equimolar mixtures of both subunits were used to measure dissociation constants for the three coupled dimerization reactions of RT in the absence and presence of saturating concentrations of the drug. The dimerization constants of the p51/p51 homodimer, the p66/p66 homodimer, and the p66/p51 heterodimer increased 600-, 50-, and 25-fold, respectively, upon binding of efavirenz. The effects of NNRTIs on RT dimerization are consistent with a thermodynamic linkage between subunit association/dissociation and inhibitor binding. Analysis of crystal structures of the p66/p51 heterodimer reveals that efavirenz binding induces small structural changes at the dimer interface.