ArticleBiochemistry2011
Role of induced fit in limiting discrimination against AZT by HIV reverse transcriptase.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 39 citations in OpenAlex.
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- Microfluidic tool for rapid functional characterization of CRISPR complexes.New biotechnology · 2022Article
- Analytical and functional aspects of protein-ligand interactions: Beyond induced fit and conformational selection.Archives of biochemistry and biophysics · 2021Review
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- Kinetic Evidence for an Induced Fit Mechanism in the Binding of the Substrate Camphor by Cytochrome P450ACS catalysis · 2021Article
- Mechanisms of inhibition of viral RNA replication by nucleotide analogs.The Enzymes · 2021Review
- Optimized incorporation of an unnatural fluorescent amino acid affords measurement of conformational dynamics governing high-fidelity DNA replication.The Journal of biological chemistry · 2020Article
- A pre-catalytic non-covalent step governs DNA polymerase β fidelity.Nucleic acids research · 2019Article
- Kinetic characterization of Cas9 enzymes.Methods in enzymology · 2019Article
- The nature of the DNA substrate influences pre-catalytic conformational changes of DNA polymerase β.The Journal of biological chemistry · 2018Article
- Mechanistic Origins of Enzyme Activation in Human Glucokinase Variants Associated with Congenital Hyperinsulinism.Biochemistry · 2018Article
- DNA Polymerase β Cancer-Associated Variant I260M Exhibits Nonspecific Selectivity toward the β-γ Bridging Group of the Incoming dNTP.Biochemistry · 2017Article
- A new general method for simultaneous fitting of temperature and concentration dependence of reaction rates yields kinetic and thermodynamic parameters for HIV reverse transcriptase specificity.The Journal of biological chemistry · 2017Article
- A Change in the Rate-Determining Step of Polymerization by the K289M DNA Polymerase β Cancer-Associated Variant.Biochemistry · 2017Article
- Rate-limiting Pyrophosphate Release by HIV Reverse Transcriptase Improves Fidelity.The Journal of biological chemistry · 2016Article
- HIV-1 Reverse Transcriptase Polymerase and RNase H (Ribonuclease H) Active Sites Work Simultaneously and Independently.The Journal of biological chemistry · 2016Article
- Recent Structural Insights into Cytochrome P450 Function.Trends in pharmacological sciences · 2016Review
- Thumb Site 2 Inhibitors of Hepatitis C Viral RNA-dependent RNA Polymerase Allosterically Block the Transition from Initiation to Elongation.The Journal of biological chemistry · 2016Article
- FRET-based assay to screen inhibitors of HIV-1 reverse transcriptase and nucleocapsid protein.Nucleic acids research · 2016Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Single turnover kinetic studies were conducted using fluorescently labeled HIV reverse transcriptase (RT) to evaluate the role of nucleotide-induced changes in enzyme structure in the selectivity against AZT in order to explore why AZT-resistant forms of the enzyme fail to significantly discriminate against AZT. Fluorescent labeling of HIV RT provided a signal to monitor the isomerization from "open" to "closed" states following nucleotide binding. We measured the rate constants governing nucleotide binding and enzyme isomerization for TTP and AZT-triphosphate by the wild-type and AZT-resistant forms of the enzyme containing the thymidine analogue mutations (TAMs). We show that the TAMs alter the kinetics of AZT incorporation by weakening ground-state nucleotide binding and decreasing the rate of chemistry relative to the wild-type enzyme. However, the slower rate of incorporation of AZT by the TAMs HIV RT is counterbalanced a lower K(m), resulting from the equilibration of the conformational change step. In contrast, the K(m) for the wild-type enzyme reflects the balance between rates of binding and incorporation so the conformational change step does not come to equilibrium. These data once again demonstrate that the rate of substrate release, limited by the reverse of the substrate-induced conformational change, is the key determinant of the role of induced fit in enzyme specificity. Mutations leading to slower rates of incorporation have the unfortunate consequence of lowering the K(m) value by allowing the conformational change step to come to equilibrium.
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Registered trials
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.