Integration Requires a Specific Interaction of the Donor DNA Terminal 5′-Cytosine with Glutamine 148 of the HIV-1 Integrase Flexible Loop
Johnson, Allison A.
Pais, Godwin C. G.
Burke, Terrence R.
MetadataShow full item record
CitationJohnson, Allison A., Webster Santos, Godwin C. G. Pais, Christophe Marchand, Ronak Amin, Terrence R. Burke, Gregory Verdine, and Yves Pommier. 2006. “Integration Requires a Specific Interaction of the Donor DNA Terminal 5′-Cytosine with Glutamine 148 of the HIV-1 Integrase Flexible Loop.” Journal of Biological Chemistry281 (1): 461–67. https://doi.org/10.1074/jbc.M511348200.
AbstractIntegration is essential for retroviral replication and gene therapy using retroviral vectors. Human immunodeficiency virus, type 1 (HIV-1), integrase specifically recognizes the terminal sequences of each long terminal repeat ( 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 DNAduplex (target or chromosomal DNA). We report that both the terminal cytosine at the protruding 5'-end of the long terminal repeats (5'-C) and the integrase residue Gln-148 are critical for strand transfer. Proximity of the 5'-C and Gln-148 was demonstrated by disulfide cross-linking. Cross- linking is inhibited by the inhibitor 5CITEP 1-( 5- chloroindol- 3- yl)- 3- hydroxy- 3-(2H-tetrazol-5- yl)- propenone. We propose that strand transfer requires a conformational change of the integrase-viral (donor) DNA-complex with formation of an H-bond between the N-3 of the 5'-C and the amine group of Gln-148. These findings have implications for the molecular mechanisms coupling 3'-processing and strand transfer as well as for the molecular pharmacology of integrase inhibitors.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41511259
- FAS Scholarly Articles