The impact of molecular manipulation in residue 114 of human immunodeficiency virus type-1 reverse transcriptase on dNTP substrate binding and viral replication

  • Van Cor-Hosmer S
  • Daddacha W
  • Kelly Z
 et al. 
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Human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) has a unique tight binding to dNTP substrates. Structural modeling of Ala-114 of HIV-1 RT suggests that longer side chains at this residue can reduce the space normally occupied by the sugar moiety of an incoming dNTP. Indeed, mutations at Ala-114 decrease the ability of RT to synthesize DNA at low dNTP concentrations and reduce the dNTP-binding affinity (Kd) of RT. However, the Kdvalues of WT and A114C RT remained equivalent with an acyclic dNTP substrate. Finally, mutant A114 RT HIV-1 vectors displayed a greatly reduced transduction in nondividing human lung fibroblasts (HLFs), while WT HIV-1 vector efficiently transduced both dividing and nondividing HLFs. Together these data support that the A114 residue of HIV-1 RT plays a key mechanistic role in the dNTP binding of HIV-1 RT and the unique viral infectivity of target cell types with low dNTP pools. © 2011 Elsevier Inc.

Author-supplied keywords

  • Cellular dNTP pools
  • DNTP binding affinity
  • HIV-1
  • Reverse transcriptase
  • Steady and presteady kinetics

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  • Sarah K. Van Cor-Hosmer

  • Waaqo Daddacha

  • Z. Kelly

  • Amy Tsurumi

  • Edward M. Kennedy

  • Baek Kim

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