3′-Processing and strand transfer catalysed by retroviral integrase in crystallo

Hare, Stephen, Maertens, Goedele N and Cherepanov, Peter (2012) 3′-Processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO Journal, 31 (13). pp. 3020-3028. ISSN 0261-4189

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Retroviral integrase (IN) is responsible for two consecutive reactions, which lead to insertion of a viral DNA copy into a host cell chromosome. Initially, the enzyme removes di- or trinucleotides from viral DNA ends to expose 3′-hydroxyls attached to the invariant CA dinucleotides (3′-processing reaction). Second, it inserts the processed 3′-viral DNA ends into host chromosomal DNA (strand transfer). Herein, we report a crystal structure of prototype foamy virus IN bound to viral DNA prior to 3′-processing. Furthermore, taking advantage of its dependence on divalent metal ion cofactors, we were able to freeze trap the viral enzyme in its ground states containing all the components necessary for 3′-processing or strand transfer. Our results shed light on the mechanics of retroviral DNA integration and explain why HIV IN strand transfer inhibitors are ineffective against the 3′-processing step of integration. The ground state structures moreover highlight a striking substrate mimicry utilized by the inhibitors in their binding to the IN active site and suggest ways to improve upon this clinically relevant class of small molecules.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Stephen Hare
Date Deposited: 22 Sep 2017 08:34
Last Modified: 02 Jul 2019 18:04
URI: http://sro.sussex.ac.uk/id/eprint/70280

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