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Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir

  1. Author:
    Tuske, S.
    Sarafianos, S. G.
    Clark, A. D.
    Ding, J. P.
    Naeger, L. K.
    White, K. L.
    Miller, M. D.
    Gibbs, C. S.
    Boyer, P. L.
    Clark, P.
    Wang, G.
    Gaffney, B. L.
    Jones, R. A.
    Jerina, D. M.
    Hughes, S. H.
    Arnold, E.

  2. Author Address

    Arnold, E, Rutgers State Univ, Ctr Adv Biotechnol & Med, 679 Hoes Lane, Piscataway, NJ 08854 USA Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem & Biol Chem, Piscataway, NJ 08854 USA. Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biol & Cell Biol, Key Lab Proteom, Shanghai 200032, Peoples R China. Gilead Sci Inc, Foster City, CA 94404 USA. NCI, HIV Drug Resistance Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA.
    1. Year: 2004
  2. Journal: Nature Structural & Molecular Biology
    1. 11
    2. 5
    3. Pages: 469-474
  4. Type of Article: Article
  1. Abstract:

    Tenofovir, also known as PMPA, R-9-(2-(phosphonomethoxypropyl)adenine, is a nucleotide reverse transcriptase (RT) inhibitor. We have determined the crystal structures of two related complexes of HIV-1 RT with template primer and tenofovir: (i) a ternary complex at a resolution of 3.0 Angstrom of RT crosslinked to a dideoxy-terminated DNA with tenofovir-diphosphate bound as the incoming substrate; and (ii) a RT DNA complex at a resolution of 3.1 Angstrom with tenofovir at the 3 primer terminus. The tenofovir nucleotide in the tenofovir-terminated structure seems to adopt multiple conformations. Some nucleoside reverse transcriptase inhibitors, including 3TC and AZT, have elements (handles) that project beyond the corresponding elements on normal dNTPs (the substrate envelope). HIV-1 RT resistance mechanisms to AZT and 3TC take advantage of these handles; tenofovir's structure lacks handles that could protrude through the substrate envelope to cause resistance

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