Retroviral intasome assembly and inhibition of DNA strand transfer

Hare, Stephen, Gupta, Saumya Shree, Valkov, Eugene, Engelman, Alan and Cherepanov, Peter (2010) Retroviral intasome assembly and inhibition of DNA strand transfer. Nature, 464 (7286). pp. 232-236. ISSN 0028-0836

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Stephen Hare
Date Deposited: 21 Sep 2017 14:53
Last Modified: 21 Sep 2017 14:53
URI: http://sro.sussex.ac.uk/id/eprint/70287
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