Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK.
Nature. 2010 Mar 11;464(7286):232-6. doi: 10.1038/nature08784. Epub 2010 Jan 31.
Integrase is an essential retroviral enzyme that binds both termini of linear viral DNA and inserts them into a host cell chromosome. The structure of full-length retroviral integrase, either separately or in complex with DNA, has been lacking. Furthermore, although clinically useful inhibitors of HIV integrase have been developed, their mechanism of action remains speculative. Here we present a crystal structure of full-length integrase from the prototype foamy virus in complex with its cognate DNA. The structure shows the organization of the retroviral intasome comprising an integrase tetramer tightly associated with a pair of viral DNA ends. All three canonical integrase structural domains are involved in extensive protein-DNA and protein-protein interactions. The binding of strand-transfer inhibitors displaces the reactive viral DNA end from the active site, disarming the viral nucleoprotein complex. Our findings define the structural basis of retroviral DNA integration, and will allow modelling of the HIV-1 intasome to aid in the development of antiretroviral drugs.
整合酶是一种必需的逆转录病毒酶，可结合线性病毒 DNA 的两端，并将其插入宿主细胞染色体中。全长逆转录病毒整合酶的结构，无论是单独存在还是与 DNA 复合，都一直缺失。此外，尽管已经开发出临床上有用的 HIV 整合酶抑制剂，但它们的作用机制仍在推测之中。在这里，我们展示了与同源 DNA 复合的原型泡沫病毒全长整合酶的晶体结构。该结构显示了逆转录酶整合酶体的组织，由紧密关联的四聚体整合酶和一对病毒 DNA 末端组成。所有三个典型的整合酶结构域都参与广泛的蛋白-DNA 和蛋白-蛋白相互作用。链转移抑制剂的结合会将反应性的病毒 DNA 末端从活性位点置换出来，使病毒核蛋白复合物失去作用。我们的发现定义了逆转录病毒 DNA 整合的结构基础，并将允许对 HIV-1 整合酶体进行建模，以帮助开发抗逆转录病毒药物。
