Article

Nature 464, 232-236 (11 March 2010) | doi:10.1038/nature08784; Received 10 November 2009; Accepted 6 January 2010; Published online 31 January 2010

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.
  4. Present addresses: Hannover Biomedical Research School, D-30625 Hannover, Germany (S.S.G.); School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia (E.V.).

Correspondence to: Peter Cherepanov1 Correspondence and requests for materials should be addressed to P.C. (Email: p.cherepanov@imperial.ac.uk).

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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.

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