A supramolecular assembly mediates lentiviral DNA integration.
A supramolecular assembly mediates lentiviral DNA integration.
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DOI：
10.1126/science.aah7002
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发表时间：
2017-01-06
期刊：
影响因子：
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通讯作者：
Cherepanov P
中科院分区：
文献类型：
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作者：
Ballandras-Colas A;Maskell DP;Serrao E;Locke J;Swuec P;Jónsson SR;Kotecha A;Cook NJ;Pye VE;Taylor IA;Andrésdóttir V;Engelman AN;Costa A;Cherepanov P
逆转录病毒整合酶（IN）在整合体核蛋白复合物中起作用，催化病毒DNA插入细胞染色质。使用冷冻电子显微镜，我们现在以4.9 μ m的分辨率显示功能性梅迪-维斯纳慢病毒整合体。该整合体由IN的同十六聚体组成，具有四聚体的四聚体结构，具有八种结构不同类型的IN原聚体，支持两个有催化活性的亚基。保守的intasomal核心，以前观察到在简单的逆转录病毒系统中，形成两个IN四聚体之间，与一对C-末端结构域从侧翼四聚体完成突触界面。我们的研究结果解释了HIV-1 IN如何自我缔合成高阶多聚体，可以形成功能性整合体，调和早期HIV-1 IN的大部分生化和结构数据，并为HIV-1 IN抑制剂的设计提供慢病毒平台。
Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 Å resolution. The intasome comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture featuring eight structurally distinct types of IN protomers supporting two catalytically competent subunits. The conserved intasomal core, previously observed in simpler retroviral systems, is formed between two IN tetramers, with a pair of C-terminal domains from flanking tetramers completing the synaptic interface. Our results explain how HIV-1 IN, which self-associates into higher order multimers, can form a functional intasome, reconcile the bulk of early HIV-1 IN biochemical and structural data, and provide a lentiviral platform for design of HIV-1 IN inhibitors.