Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type 1 reverse transcriptase
Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type 1 reverse transcriptase
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DOI：
10.1073/pnas.121055998
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发表时间：
2001-06-19
影响因子：
11.1
通讯作者：
Goff, SP
中科院分区：
文献类型：
--
作者：
Tachedjian, G;Orlova, M;Goff, SP
非核苷类逆转录酶抑制剂(NNRTI)是HIV-1逆转录酶(RT)的变构抑制剂，酵母双杂交试验表明，在许多药物存在下培养的酵母显示出HIV-1 RT的p66和p51亚单位显著增加的相关性。通过RT将耐药突变引入p66结构来增强所需的药物结合，否定了增强效果。这些药物还可以诱导二聚化缺陷突变体的异二聚化。酵母裂解物RT亚基的免疫共沉淀证实了药物诱导的异源二聚体的形成。体外结合研究表明，NNRTI可以与p66紧密结合，但不能与p51结合，然后介导随后的异源二聚化。这项研究证明了NNRTIs对RT亚基组装的意想不到的影响。
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV type 1 (HIV-1) reverse transcriptase (RT), Yeast grown in the presence of many of these drugs exhibited dramatically increased association of the p66 and p51 subunits of the HIV-1 RT as reported by a yeast two-hybrid assay. The enhancement required drug binding by RT introduction of a drug-resistance mutation into the p66 construct negated the enhancement effect. The drugs could also induce heterodimerization of dimerization defective mutants. Coimmunoprecipitation of RT subunits from yeast lysates confirmed the induction of heterodimer formation by the drugs. In vitro-binding studies indicate that NNRTIs can bind tightly to p66 but not p51 and then mediate subsequent heterodimerization. This study demonstrates an unexpected effect of NNRTIs on the assembly of RT subunits.