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Molecular Pharmacology

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Research ArticleArticle

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

Allison A. Johnson, Christophe Marchand, Sachindra S. Patil, Roberta Costi, Roberto Di Santo, Terrence R. Burke Jr. and Yves Pommier
Molecular Pharmacology March 2007, 71 (3) 893-901; DOI: https://doi.org/10.1124/mol.106.030817
Allison A. Johnson
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Christophe Marchand
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Sachindra S. Patil
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Roberta Costi
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Roberto Di Santo
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Terrence R. Burke Jr.
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Yves Pommier
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Abstract

HIV-1 integrase binds site-specifically to the ends of the viral cDNA. We used two HIV-1 integrase-DNA cross-linking assays to probe the binding sites of integrase inhibitors from different chemical families and with different strand transfer selectivities. The disulfide assay probes cross-linking between the integrase residue 148 and the 5′-terminal cytosine of the viral cDNA, and the Schiff base assay probes cross-linking between an integrase lysine residue and an abasic site placed at selected positions in the viral cDNA. Cross-linking interference by eight integrase inhibitors shows that the most potent cross-linking inhibitors are 3′-processing inhibitors, indicating that cross-linking assays probe the donor viral cDNA (donor binding site). In contrast, strand transfer-selective inhibitors provide weak cross-linking interference, consistent with their binding to a specific acceptor (cellular DNA) site. Docking and crystal structure studies illustrate specific integrase-inhibitor contacts that prevent cross-linking formation. Four inhibitors that prevented Schiff base cross-linking to the conserved 3′-terminal adenine position were examined for inhibition at various positions within the terminal 21 bases of the viral cDNA. Two of them selectively inhibited upper strand cross-linking, whereas the other two had a more global effect on integrase-DNA binding. These findings have implications for elucidating inhibitor binding sites and mechanisms of action. The cross-linking assays also provide clues to the molecular interactions between integrase and the viral cDNA.

Footnotes

  • This research was supported by the National Institutes of Health Intramural Program, Center for Cancer Research, National Cancer Institute.

  • A.A.J. and C.M. contributed equally to this work

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.030817.

  • ABBREVIATIONS: LTR, long terminal repeat; 3′-P, 3′-processing; MOPS, 4-morpholinepropanesulfonic acid; DKA, diketo acid; l-CA, l-chicoric acid repeat; ST, strand transfer.

    • Received September 13, 2006.
    • Accepted December 14, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (3)
Molecular Pharmacology
Vol. 71, Issue 3
1 Mar 2007
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Research ArticleArticle

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

Allison A. Johnson, Christophe Marchand, Sachindra S. Patil, Roberta Costi, Roberto Di Santo, Terrence R. Burke and Yves Pommier
Molecular Pharmacology March 1, 2007, 71 (3) 893-901; DOI: https://doi.org/10.1124/mol.106.030817

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Research ArticleArticle

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

Allison A. Johnson, Christophe Marchand, Sachindra S. Patil, Roberta Costi, Roberto Di Santo, Terrence R. Burke and Yves Pommier
Molecular Pharmacology March 1, 2007, 71 (3) 893-901; DOI: https://doi.org/10.1124/mol.106.030817
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