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

被引:11
|
作者
Van Cor-Hosmer, Sarah K. [1 ]
Daddacha, Waaqo [1 ]
Kelly, Z. [1 ]
Tsurumi, Amy [1 ]
Kennedy, Edward M. [1 ]
Kim, Baek [1 ]
机构
[1] Univ Rochester, Dept Microbiol & Immunol, Med Ctr, Rochester, NY 14648 USA
关键词
HIV-1; Reverse transcriptase; dNTP binding affinity; Cellular dNTP pools; Steady and presteady kinetics; MURINE LEUKEMIA-VIRUS; DNA-SYNTHESIS; AMINO-ACID; DRUG-RESISTANCE; STERIC GATE; CELL-CYCLE; HIV-1; FIDELITY; LAMIVUDINE; MACROPHAGE;
D O I
10.1016/j.virol.2011.11.004
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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 (K-d) of RT. However, the K-d values 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. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:393 / 401
页数:9
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