Ballandras-Colas Allison, Maskell Daniel P, Serrao Erik, Locke Julia, Swuec Paolo, Jónsson Stefán R, Kotecha Abhay, Cook Nicola J, Pye Valerie E, Taylor Ian A, Andrésdóttir Valgerdur, Engelman Alan N, Costa Alessandro, Cherepanov Peter
Chromatin Structure and Mobile DNA, The Francis Crick Institute, London, NW1 1AT, UK.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Science. 2017 Jan 6;355(6320):93-95. doi: 10.1126/science.aah7002.
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 angstrom 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.
逆转录病毒整合酶（IN）在整合体核蛋白复合物中发挥作用，催化病毒DNA插入细胞染色质。利用冷冻电子显微镜，我们现在以4.9埃的分辨率可视化了功能性梅迪-维斯纳慢病毒整合体。整合体由IN的同型十六聚体组成，具有四聚体的四聚体结构，其特征是有八种结构不同类型的IN原聚体，支持两个具有催化活性的亚基。在更简单的逆转录病毒系统中先前观察到的保守整合体核心，形成于两个IN四聚体之间，来自侧翼四聚体的一对C末端结构域完成了突触界面。我们的结果解释了自组装成高阶多聚体的HIV-1 IN如何形成功能性整合体，协调了大部分早期HIV-1 IN的生化和结构数据，并为设计HIV-1 IN抑制剂提供了一个慢病毒平台。
