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• W1569123141 abstract "Human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) catalyzes DNA synthesis by an ordered sequential mechanism. After template-primer (T·P) binds to free enzyme, the deoxynucleoside triphosphate to be incorporated binds to the RT and T·P binary complex (RTT·P). After incorporation of the bound nucleotide, catalytic cycling is limited either by a conformational change (for processive synthesis) or release of the enzyme from the extended T·P (for single-nucleotide incorporation). To explore cycling through these alternate rate-limiting steps, we determined kinetic parameters for single-nucleotide incorporation by HXB2R HIV-1 RT with chain-terminating nucleotide substrates 3′-azido-3′-deoxythymidine triphosphate (AZTTP) and dideoxythymidine triphosphate on a homopolymeric T·P system, poly(rA)-oligo(dT)16. Inhibition of processive deoxythymidine monophosphate incorporation by these chain-terminating substrates was also examined. Because AZTTP is a substrate, its Kmshould be equivalent to Ki, and since Kmfor AZTTP should be influenced by the dissociation rate constant for RTT·P, we examined the effect of altering RTT·Pdissociation on AZTTP kinetic parameters. The dissociation rate constant was modulated by making use of different T·P substrates, viral sources of RT, and a mutant RT altered at a residue that perturbs T·P binding.As expected from earlier work, the time course of AZTMP incorporation on poly(rA)-oligo(dT)16was biphasic, with a burst followed by a slower steady-state phase representing kcat(0.42 min−1) which was similar to the rate constant for RTT·Pdissociation. Additionally, Kmfor AZTTP (110 nM) was lower than its equilibrium dissociation constant (1200 nM). AZTTP inhibition (KiAZTTP) of processive dTMP incorporation and incorporation of a single nucleotide were similar. However, a simple correlation between the RTT·Pdissociation rate constant and KiAZTTPwas not observed. These results indicate that a simple ordered model for single-nucleotide incorporation is inadequate and that different forms of RTT·Pexist which can limit catalysis. The results are discussed in the context of a two-step binding reaction for T·P where the binary RTT·Pcomplex undergoes an isomerization before binding of the deoxynucleotide substrate. Human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) catalyzes DNA synthesis by an ordered sequential mechanism. After template-primer (T·P) binds to free enzyme, the deoxynucleoside triphosphate to be incorporated binds to the RT and T·P binary complex (RTT·P). After incorporation of the bound nucleotide, catalytic cycling is limited either by a conformational change (for processive synthesis) or release of the enzyme from the extended T·P (for single-nucleotide incorporation). To explore cycling through these alternate rate-limiting steps, we determined kinetic parameters for single-nucleotide incorporation by HXB2R HIV-1 RT with chain-terminating nucleotide substrates 3′-azido-3′-deoxythymidine triphosphate (AZTTP) and dideoxythymidine triphosphate on a homopolymeric T·P system, poly(rA)-oligo(dT)16. Inhibition of processive deoxythymidine monophosphate incorporation by these chain-terminating substrates was also examined. Because AZTTP is a substrate, its Kmshould be equivalent to Ki, and since Kmfor AZTTP should be influenced by the dissociation rate constant for RTT·P, we examined the effect of altering RTT·Pdissociation on AZTTP kinetic parameters. The dissociation rate constant was modulated by making use of different T·P substrates, viral sources of RT, and a mutant RT altered at a residue that perturbs T·P binding. As expected from earlier work, the time course of AZTMP incorporation on poly(rA)-oligo(dT)16was biphasic, with a burst followed by a slower steady-state phase representing kcat(0.42 min−1) which was similar to the rate constant for RTT·Pdissociation. Additionally, Kmfor AZTTP (110 nM) was lower than its equilibrium dissociation constant (1200 nM). AZTTP inhibition (KiAZTTP) of processive dTMP incorporation and incorporation of a single nucleotide were similar. However, a simple correlation between the RTT·Pdissociation rate constant and KiAZTTPwas not observed. These results indicate that a simple ordered model for single-nucleotide incorporation is inadequate and that different forms of RTT·Pexist which can limit catalysis. The results are discussed in the context of a two-step binding reaction for T·P where the binary RTT·Pcomplex undergoes an isomerization before binding of the deoxynucleotide substrate." @default.
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• W1569123141 date "1995-04-01" @default.
• W1569123141 modified "2023-09-30" @default.
• W1569123141 title "Human Immunodeficiency Virus Type 1 Reverse Transcriptase" @default.
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• W1569123141 doi "https://doi.org/10.1074/jbc.270.17.9740" @default.
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