逆转录病毒的整合酶蛋白如HIV-1催化病毒基因组向宿主基因组中的插入，在那里病毒能够在一个细胞中无限期地长久存在。因为整合是病毒复制的关键，所以整合酶一直是药物开发的一个目标，而几种抑制药物（包括raltegravir 和 elvitegravir）则被用于治疗或进行临床试验。寻找新的抗逆转录病毒药物的工作一直受阻于缺乏在基质DNA上的整合酶复合物（或称整合体）的结构。现在，来自非致病逆转录病毒（被称为“泡沫病毒原型”）的全长度逆转录病毒整合酶的晶体结构，已在与其同类病毒DNA形成的复合物中被确定。除了揭示整合反应生物化学方面的详细情况外，该结构也反映了目前所使用的抑制药物是怎样影响这一过程的。(生物谷Bioon.com)
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生物谷推荐原文出处
Nature doi:10.1038/nature08784
Retroviral intasome assembly and inhibition of DNA strand transfer
Stephen Hare1,3, Saumya Shree Gupta1,3,4, Eugene Valkov1,4, Alan Engelman2 & Peter Cherepanov1
1 Division of Medicine, Imperial College London, St-Mary’s Campus, Norfolk Place, London W2 1PG, UK
2 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
3 These authors contributed equally to this work.
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.
