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The mechanism of retroviral integration from X-ray structures of its key intermediates

机译：从关键中间体的X射线结构看逆转录病毒整合的机制

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摘要

To establish productive infection, a retrovirus must insert a DNA replica of its genome into host cell chromosomal DNA. This process is operated by the intasome, a nucleoprotein complex composed of an integrase tetramer (IN) assembled on the viral DNA ends. The intasome engages chromosomal DNA within a target capture complex to carry out strand transfer, irreversibly joining the viral and cellular DNA molecules. Although several intasome/ transpososome structures from the DDE(D) recombinase super-family have been reported, the mechanics of target DNA capture and strand transfer by these enzymes remained unclear. Here we report crystal structures of the intasome from prototype foamy virus in complex with target DNA, elucidating the pre-integration target DNA capture and post-catalytic strand transfer intermediates of the retroviral integration process. The cleft between IN dimers within the intasome accommodates chromosomal DNA in a severely bent conformation, allowing widely spaced IN active sites to access the scissile phosphodiester bonds. Our results resolve the structural basis for retroviral DNA integration and provide a framework for the design of INs with altered target sequences.
机译：为了建立生产性感染，逆转录病毒必须将其基因组的DNA复制品插入宿主细胞染色体DNA中。该过程由intasome（一种由整合在病毒DNA末端的整合酶四聚体（IN）组成的核蛋白复合物）操作。内含体与靶标捕获复合物中的染色体DNA结合以进行链转移，从而不可逆地结合病毒和细胞DNA分子。尽管已报道了来自DDE（D）重组酶超家族的几种intasome /转座体结构，但这些酶对靶DNA的捕获和链转移的机理尚不清楚。在这里，我们报告了原型泡沫病毒与目标DNA结合体中的intasome的晶体结构，阐明了逆转录病毒整合过程的整合前目标​​DNA捕获和催化后链转移中间体。 Intasome中IN二聚体之间的裂隙以严重弯曲的构型容纳染色体DNA，从而使宽间隔的IN活性位点可进入易裂的磷酸二酯键。我们的结果解决了逆转录病毒DNA整合的结构基础，并为靶序列改变的IN的设计提供了框架。

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  • 来源
    《Nature》 |2010年第7321期|p.326-329121|共5页
  • 作者

    Goedele N. Maertens; Stephen Hare; Peter Cherepanov;

  • 作者单位

    Division of Infectious Diseases, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK;

    rnDivision of Infectious Diseases, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK;

    rnDivision of Infectious Diseases, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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