專題：Nature系列
逆轉錄病毒的整合酶蛋白如HIV-1催化病毒基因組向宿主基因組中的插入，在那裡病毒能夠在一個細胞中無限期地長久存在。因為整合是病毒複製的關鍵，所以整合酶一直是藥物開發的一個目標，而幾種抑制藥物（包括raltegravir 和 elvitegravir）則被用於治療或進行臨床試驗。尋找新的抗逆轉錄病毒藥物的工作一直受阻於缺乏在基質DNA上的整合酶複合物（或稱整合體）的結構。現在，來自非致病逆轉錄病毒（被稱為「泡沫病毒原型」）的全長度逆轉錄病毒整合酶的晶體結構，已在與其同類病毒DNA形成的複合物中被確定。除了揭示整合反應生物化學方面的詳細情況外，該結構也反映了目前所使用的抑制藥物是怎樣影響這一過程的。(生物谷Bioon.com)
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生物谷推薦原文出處
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.