...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >The thumb domain of the P51-subunit is essential for activation of HIV reverse transcriptase.
【24h】

The thumb domain of the P51-subunit is essential for activation of HIV reverse transcriptase.

机译：P51亚基的拇指域对于激活HIV逆转录酶至关重要。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The biologically relevant and active form of human immunodeficiency virus reverse transcriptase is a heterodimer produced in a two-step dimerization process. Dimerization involves first the rapid association of the two subunits, followed by a slow conformational change yielding a fully active form. In the present study, we demonstrate that the interaction between the thumb domain of p51 and the RNase-H domain of p66 plays a major role in an essential conformational change required for proper folding of the primer/template and the tRNA-binding site, for maturation and for activation of heterodimeric reverse transcriptase. A synthetic peptide derived from the sequence within the thumb domain of p51, which forms the interface with the RNase-H domains of p66, binds heterodimeric reverse transcriptase with an apparent dissociation constant in the nanomolar range and selectively inhibits activation of heterodimeric reverse transcriptase with an inhibition constant of 1.2 microM. A detailed study of the mechanism of inhibition reveals that this peptide does not require dissociation of heterodimeric RT for efficient inhibition and does not affect subunit association, but interferes with the conformational change required for activation of heterodimeric reverse transcriptase, resulting in a decrease in the affinity of reverse transcriptase for the tRNA and an increase in the stability of the primer/template/reverse transcriptase complex. We have previously proposed that the dimeric nature of reverse transcriptase represents an interesting target for the design of antiviral agents. On the basis of this work, we propose that the conformational changes involved in the activation of reverse transcriptase similarly represent an important target for the design of novel antiviral compounds.
机译：人类免疫缺陷病毒逆转录酶的生物学相关和活性形式是在两步二聚过程中产生的异二聚体。二聚化首先涉及两个亚基的快速缔合，然后缓慢的构象变化产生完全活性的形式。在本研究中，我们证明了p51拇指结构域与p66 RNase-H结构域之间的相互作用在适当折叠引物/模板和tRNA结合位点所需的必要构象变化中起着重要作用。成熟并用于激活异二聚体逆转录酶。衍生自p51拇指域内序列的合成肽，与p66的RNase-H域形成界面，结合异二聚体逆转录酶，其表观解离常数在纳摩尔范围内，并选择性抑制异二聚体逆转录酶的激活。抑制常数为1.2 microM。抑制机理的详细研究表明，该肽不需要解离异二聚体RT即可有效抑制，并且不影响亚基缔合，但会干扰激活异二聚体逆转录酶所需的构象变化，从而导致亲和力降低tRNA的逆转录酶的表达和引物/模板/逆转录酶复合物的稳定性增加。我们以前曾提出逆转录酶的二聚体性质代表了抗病毒剂设计的有趣目标。在这项工作的基础上，我们建议参与逆转录酶激活的构象变化同样代表了新型抗病毒化合物设计的重要目标。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号