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The mechanism of retroviral DNA integration through X-ray structures of its key intermediates

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To establish successful infection, a retrovirus must insert a DNA replica of its genome into host cell chromosomal DNA . This process is orchestrated by integrase (IN), a viral enzyme that belongs to the DDE (D nucleotidyltransferase/transposase superfamily. Following reverse transcription,IN catalyses two essential reactions, 3´- end processing and strand transfer, acting upon both ends of the linear viral DNA . To carry out these functions IN synapses the viral DNA ends forming a highly stable nucleoprotein complex, termed intasome. Upon nuclear entry, the intasome engages host chromosomal DNA within a target capture complex to execute strand transfer, irreversibly joining the viral and cellular DNA molecules. We recently reported a crystal structure of the prototype foamy virus intasome comprising a tetramer of IN assembled on processed viral DNA ends (Hare et al., Nature, 2010, 464:232-6). The structure revealed for the first time a fully assembled IN active site, engaged with the 3´ end of the viral DNA and a pair of metal cations. We now determined crystal structures of the viral nucleoprotein complex prior to 3´-processing and of the intasome bound to target DNA within the pre-strand transfer and post-catalytic intermediates (Maertens et al., Nature, 2010, 468: 326-329; Hare et al., in preparation). Collectively, these structures illustrate all key stages of the retroviral DNA integration process, elucidate the mechanics of the IN active site and moreover provide a framework for the design of INs with altered target sequences.

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