Structure of human RNase h1 complexed with an RNA/DNA hybrid: Insight into HIV reverse transcription
Structure of human RNase h1 complexed with an RNA/DNA hybrid: Insight into HIV reverse transcription
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DOI：
10.1016/j.molcel.2007.08.015
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发表时间：
2007-10-26
期刊：
影响因子：
16
通讯作者：
Yang, Wei
中科院分区：
文献类型：
--
作者：
Nowotny, Marcin;Gaidamakov, Sergei A.;Yang, Wei
我们在这里报告的晶体结构的人核糖核酸酶H1与RNA/DNA底物复合。不像B。人RNase H1具有一个碱性突起，形成DNA结合通道，并与保守的磷酸结合口袋一起赋予B型和2 '-脱氧DNA特异性。RNA链被四个连续的2 '-OH基团识别，并通过双金属离子机制切割。虽然RNA酶H1总体上带正电荷，但底物界面在性质上是中性至酸性的，这可能有助于催化特异性。易断裂的磷酸根和两个催化金属离子的位置是相互依赖和高度耦合的。HIV逆转录酶（RT）与RNA/DNA在其RNase H活性位点的建模表明，底物不能同时占据聚合酶活性位点，必须经历构象变化，在两个催化中心之间切换。容纳这种构象变化的区域提供了开发HIV特异性抑制剂的靶点。
We report here crystal structures of human RNase H1 complexed with an RNA/DNA substrate. Unlike B. halodurans RNase H1, human RNase H1 has a basic protrusion, which forms a DNA binding channel and together with the conserved phosphate-binding pocket confers specif icity for the B form and 2'-deoxy DNA. The RNA strand is recognized by four consecutive 2'-OH groups and cleaved by a two-metal ion mechanism. Although RNase H1 is overall positively charged, the substrate interface is neutral to acidic in character, which likely contributes to the catalytic specificity. Positions of the scissile phosphate and two catalytic metal ions are interdependent and highly coupled. Modeling of HIV reverse transcriptase (RT) with RNA/DNA in its RNase H active site suggests that the substrate cannot simultaneously occupy the polymerase active site and must undergo a conformational change to toggle between the two catalytic centers. The region that accommodates this conformational change offers a target to develop HIV-specific inhibitors.