ArticleProceedings of the National Academy of Sciences of the United States of America2010
Nucleotide-dependent conformational change governs specificity and analog discrimination by HIV reverse transcriptase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 91 citations in OpenAlex.
- Slow PPThe Journal of biological chemistry · 2026Article
- Protein loops are major contributors to DNA strand separation and high-fidelity substrate recognition for DNA methyltransferase CcrM.The Journal of biological chemistry · 2026Article
- Understanding the Fidelity and Specificity of DNA Polymerase I.ACS omega · 2025Article
- Article
- Modifying the Basicity of the dNTP Leaving Group Modulates Precatalytic Conformational Changes of DNA Polymerase β.Biochemistry · 2024Article
- High fidelity DNA strand-separation is the major specificity determinant in DNA methyltransferase CcrM's catalytic mechanism.Nucleic acids research · 2023Article
- Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurposing.Drug discovery today · 2022Review
- Structural and Molecular Kinetic Features of Activities of DNA Polymerases.International journal of molecular sciences · 2022Review
- Leveraging intrinsic flexibility to engineer enhanced enzyme catalytic activity.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Microfluidic tool for rapid functional characterization of CRISPR complexes.New biotechnology · 2022Article
- Mechanisms of inhibition of viral RNA replication by nucleotide analogs.The Enzymes · 2021Review
- Remdesivir Is Effective in Combating COVID-19 because It Is a Better Substrate than ATP for the Viral RNA-Dependent RNA Polymerase.iScience · 2020Article
- Optimized incorporation of an unnatural fluorescent amino acid affords measurement of conformational dynamics governing high-fidelity DNA replication.The Journal of biological chemistry · 2020Article
- Enhanced enzyme kinetics of reverse transcriptase variants cloned from animals infected with SIVmac239 lacking viral protein X.The Journal of biological chemistry · 2020Article
- Rate-limiting pyrophosphate release by hepatitis C virus polymerase NS5B improves fidelity.The Journal of biological chemistry · 2020Article
- Using single-molecule FRET to probe the nucleotide-dependent conformational landscape of polymerase β-DNA complexes.The Journal of biological chemistry · 2020Article
- Exploring the Reaction Mechanism of HIV Reverse Transcriptase with a Nucleotide Substrate.The journal of physical chemistry. B · 2020Article
- A pre-catalytic non-covalent step governs DNA polymerase β fidelity.Nucleic acids research · 2019Article
- Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV-1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine.Protein science : a publication of the Protein Society · 2019Article
- Non-nucleoside Reverse Transcriptase Inhibitors Inhibit Reverse Transcriptase through a Mutually Exclusive Interaction with Divalent Cation-dNTP Complexes.Biochemistry · 2019Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Single turnover studies on HIV reverse transcriptase suggest that nucleoside analogs bind more tightly to the enzyme than normal substrates, contrary to rational structural predictions. Here we resolve these controversies by monitoring the kinetics of nucleotide-induced changes in enzyme structure. We show that the specificity constant for incorporation of a normal nucleotide (dCTP) is determined solely by the rate of binding (including isomerization) because isomerization to the closed complex commits the substrate to react. In contrast, a nucleoside analog (3TC-TP, triphosphate form of lamivudine) is incorporated slowly, allowing the conformational change to come to equilibrium and revealing tight nucleotide binding. Our data reconcile previously conflicting reports suggesting that nucleotide analogs bind tighter than normal nucleotides. Rather, dCTP and 3TC-TP bind with nearly equal affinities, but the binding of dCTP never reaches equilibrium. Discrimination against 3TC-TP is based on the slower rate of incorporation due to misalignment of the substrate and/or catalytic residues.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.