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M511348200v1
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Papers In Press, published online ahead of print October 27, 2005
J. Biol. Chem, 10.1074/jbc.M511348200
Submitted on October 19, 2005
Accepted on October 27, 2005

HIV-1 integration requires the viral DNA end (5'-C) interaction with glutamine 148 of the integrase flexible loop

Allison A. Johnson, Webster Santos, Godwin C. G. Pais, Christophe Marchand, Ronak Amin, Terrence R. Burke . Jr, Gregory Verdine, and Yves Pommier

Laboratory of Molecular Pharmacology, National Cancer Insitute, National Institutes of Health, Bethesda, MD 20892

Corresponding Author: pommier{at}nih.gov

Integration is essential for retroviral replication and gene therapy using retroviral vectors. HIV-1 integrase specifically recognizes the terminal sequences of each long terminal repeats (LTR) and cleaves the 3’-end terminal dinucleotide 5’-GT. The exposed 3’-hydroxyl is then positioned for nucleophilic attack and subsequent strand transfer into another DNA duplex (target or chromosomal DNA). We report that both the terminal cytosine at the protruding 5’-end of the LTR (5’-C) and the integrase residue Q148 are critical for strand transfer. Proximity of the 5’-C and Q148 was demonstrated by disulfide crosslinking. Crosslinking is inhibited by the inhibitor 5CITEP. We propose that strand transfer requires a conformational change of the integrase-viral (donor) DNA complex with formation of an H-bond between the N3 of the 5’-C and the amine group of Q148. These findings have implications for the molecular mechanisms coupling 3’-processing and strand transfer as well as for the molecular pharmacology of integrase inhibitors.


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