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Structures of HIV-1 reverse transcriptase with pre- and post- translocation AZTMP-terminated DNA

  1. Author:
    Sarafianos, S. G.
    Clark, A. D.
    Das, K.
    Tuske, S.
    Birktoft, J. J.
    Ilankumaran, P.
    Ramesha, A. R.
    Sayer, J. M.
    Jerina, D. M.
    Boyer, P. L.
    Hughes, S. H.
    Arnold, E.

  2. Author Address

    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 & Chem Biol, Piscataway, NJ 08854 USA NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA NCI, HIV Drug Reistance Program, Frederick, MD 21702 USA Arnold E Rutgers State Univ, Ctr Adv Biotechnol & Med, 679 Hoes Lane, Piscataway, NJ 08854 USA
    1. Year: 2002
  2. Journal: Embo Journal
    1. 21
    2. 23
    3. Pages: 6614-6624
  4. Type of Article: Article
  1. Abstract:

    AZT (3'-azido-3'-deoxythymidine) resistance involves the enhanced excision of AZTMP from the end of the primer strand by HIV-1 reverse transcriptase. This reaction can occur when an AZTMP-terminated primer is bound at the (n) under bar ucleotide-binding site (pretranslocation complex N) but not at the '(p) under bar riming' site (post-translocation complex P). We determined the crystal structures of N and P complexes at 3.0 and 3.1 Angstrom resolution. These structures provide insight into the structural basis of AZTMP excision and the mechanism of translocation. Docking of a dNTP in the P complex structure suggests steric crowding in forming a stable ternary complex that should increase the relative amount of the N complex, which is the substrate for excision. Structural differences between complexes N and P suggest that the conserved YMDD loop is involved in translocation, acting as a springboard that helps to propel the primer terminus from the N to the P site after dNMP incorporation.

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