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Retroviral intasome assembly and inhibition of DNA strand transfer

DOI: 10.1038/nature08784 DOI Help
PMID: 20118915 PMID Help

Authors: Saumya Shree Gupta (Division of Medicine, Imperial College London) , Eugene Valkov (Division of Medicine, Imperial College London) , Alan Engelman (Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,) , Peter Cherepanov (Division of Medicine, Imperial College London) , Stephen Hare (Division of Medicine, Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature

State: Published (Approved)
Published: January 2010

Open Access Open Access

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.

Journal Keywords: DNA; Viral; HIV-1; Integrases; Models; Molecular; Protein; Tertiary; Retroviridae

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography