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Structure of HIV-1 Reverse Transcriptase with the Inhibitor beta-Thujaplicinol Bound at the RNase H Active Site

  1. Author:
    Himmel, D. M.
    Maegley, K. A.
    Pauly, T. A.
    Bauman, J. D.
    Das, K.
    Dharia, C.
    Clark, A. D.
    Ryan, K.
    Hickey, M. J.
    Love, R. A.
    Hughes, S. H.
    Bergqvist, S.
    Arnold, E.

  2. Author Address

    Himmel, Daniel M.; Bauman, Joseph D.; Das, Kalyan, Dharia, Chhaya, Clark, Arthur D., Jr.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Himmel, Daniel M.; Bauman, Joseph D.; Das, Kalyan, Dharia, Chhaya, Clark, Arthur D., Jr.; Arnold, Eddy] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [Maegley, Karen A.; Pauly, Tom A.; Ryan, Kevin, Hickey, Michael J.; Love, Robert A.; Bergqvist, Simon] Pfizer Global Res & Dev, La Jolla Labs, San Diego, CA 92121 USA. [Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA.
    1. Year: 2009
  2. Journal: Structure
    1. 17
    2. 12
    3. Pages: 1625-1635
  4. Type of Article: Article
  5. ISSN: 0969-2126
  1. Abstract:

    Novel inhibitors are needed to counteract the rapid emergence of drug-resistant HIV variants. HIV-1 reverse transcriptase (RT) has both DNA polymerase and RNase H (RNH) enzymatic activities, but approved drugs that inhibit RT target the polymerase. Inhibitors that act against new targets, such as RNH, should be effective against all of the current drug-resistant variants. Here, we present 2.80 angstrom and 2.04 angstrom resolution crystal structures of an RNH inhibitor, beta-thujaplicinol, bound at the RNH active site of both HIV-1 RT and an isolated RNH domain. beta-thujaplicinol chelates two divalent metal ions at the RNH active site. We provide biochemical evidence that beta-thujaplicinol is a slow-binding RNH inhibitor with noncompetitive kinetics and suggest that it forms a tropylium ion that interacts favorably with RT and the RNA:DNA substrate.

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  2. DOI: 10.1016/j.str.2009.09.016
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