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.).

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.