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Identifying and Characterizing a Functional HIV-1 Reverse Transcriptase-binding Site on Integrase

  1. Author:
    Wilkinson, T. A.
    Januszyk, K.
    Phillips, M. L.
    Tekeste, S. S.
    Zhang, M.
    Miller, J. T.
    Le Grice, S.
    Clubb, R. T.
    Chow, S. A.

  2. Author Address

    Wilkinson, Thomas A.; Tekeste, Shewit S.; Zhang, Min, Chow, Samson A.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Januszyk, Kurt, Phillips, Martin L.; Clubb, Robert T.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Miller, Jennifer T.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA.
    1. Year: 2009
  2. Journal: Journal of Biological Chemistry
    1. 284
    2. 12
    3. Pages: 7931-7936
  4. Type of Article: Article
  1. Abstract:

    Integrase (IN) from human immunodeficiency virus, type 1 (HIV-1) exerts pleiotropic effects in the viral replication cycle. Besides integration, IN mutations can impact nuclear import, viral maturation, and reverse transcription. IN and reverse transcriptase (RT) interact in vitro, and the IN C-terminal domain (CTD) is both necessary and sufficient for binding RT. We used nuclear magnetic resonance spectroscopy to identify a putative RT-binding surface on the IN CTD, and surface plasmon resonance to obtain kinetic parameters and the binding affinity for the IN-RT interaction. An IN K258A substitution that disrupts reverse transcription in infected cells is located at the putative RT-binding surface, and we found that this substitution substantially weakens IN CTD-RT interactions. We also identified two additional IN amino acid substitutions located at the putative RT-binding surface (W243E and V250E) that significantly impair viral replication in tissue culture. These results strengthen the notion that IN-RT interactions are biologically relevant during HIV-1 replication and also provide insights into this interaction at the molecular level.

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External Sources

  1. PMID: 19150986

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