ArticleNucleic acids research2014
Mechanism of allosteric inhibition of HIV-1 reverse transcriptase revealed by single-molecule and ensemble fluorescence.
Article in Nucleic acids research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 46 citations in OpenAlex.
- How Do Modulators Affect the Orthosteric and Allosteric Binding Pockets?ACS chemical neuroscience · 2022Article
- Avoiding Drug Resistance in HIV Reverse Transcriptase.Chemical reviews · 2021Review
- Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.Chemical reviews · 2021Review
- ACE2, the Receptor that Enables Infection by SARS-CoV-2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators.ChemMedChem · 2020Review
- Distinct Conformational States Underlie Pausing during Initiation of HIV-1 Reverse Transcription.Journal of molecular biology · 2020Article
- Small Conformational Changes Underlie Evolution of Resistance to NNRTI in HIV Reverse Transcriptase.Biophysical journal · 2020Article
- Efavirenz Metabolism: Influence of Polymorphic CYP2B6 Variants and Stereochemistry.Drug metabolism and disposition: the biological fate of chemicals · 2019Review
- Conformational Changes in HIV-1 Reverse Transcriptase that Facilitate Its Maturation.Structure (London, England : 1993) · 2019Article
- Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase.Antimicrobial agents and chemotherapy · 2019Article
- Non-nucleoside Reverse Transcriptase Inhibitors Inhibit Reverse Transcriptase through a Mutually Exclusive Interaction with Divalent Cation-dNTP Complexes.Biochemistry · 2019Article
- The Utility of Efavirenz-based Prophylaxis Against HIV Infection. A Systems Pharmacological Analysis.Frontiers in pharmacology · 2019Article
- DnaG Primase-A Target for the Development of Novel Antibacterial Agents.Antibiotics (Basel, Switzerland) · 2018Review
- A computational study for rational HIV-1 non-nucleoside reverse transcriptase inhibitor selection and the discovery of novel allosteric pockets for inhibitor design.Bioscience reports · 2018Article
- The structure of FIV reverse transcriptase and its implications for non-nucleoside inhibitor resistance.PLoS pathogens · 2018Article
- The HIV-1 p66 homodimeric RT exhibits different conformations in the binding-competent and -incompetent NNRTI site.Proteins · 2017Article
- Bacterial DnaB helicase interacts with the excluded strand to regulate unwinding.The Journal of biological chemistry · 2017Article
- Pausing kinetics dominates strand-displacement polymerization by reverse transcriptase.Nucleic acids research · 2017Article
- Physiological MgBiochemistry · 2017Article
- DNA binding proteins explore multiple local configurations during docking via rapid rebinding.Nucleic acids research · 2016Article
- Modeling the functional state of the reverse transcriptase of hepatitis B virus and its application to probing drug-protein interaction.BMC bioinformatics · 2016Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are routinely used to treat HIV-1 infection, yet their mechanism of action remains unclear despite intensive investigation. In this study, we developed complementary single-molecule fluorescence and ensemble fluorescence anisotropy approaches to discover how NNRTIs modulate the intra-molecular conformational changes and inter-molecular dynamics of RT-template/primer (T/P) and RT-T/P-dNTP complexes. We found that NNRTI binding to RT induces opening of the fingers and thumb subdomains, which increases the dynamic sliding motion of the enzyme on the T/P and reduces dNTP binding affinity. Further, efavirenz promotes formation of the E138-K101 salt bridge between the p51 and p66 subunits of RT, which contributes to opening of the thumb/fingers subdomains. Engineering a more polar salt bridge between p51 and p66 resulted in even greater increases in the thumb/fingers opening, RT sliding, dNTP binding disruption and in vitro and in vivo RT inhibition than were observed with wild-type RT. We also observed that K103N, a clinically relevant NNRTI resistance mutation, does not prevent binding between efavirenz and RT-T/P but instead allows formation of a stable and productive RT-T/P-dNTP complex, possibly through disruption of the E138-K101 salt bridge. Collectively, these data describe unique structure-activity-resistance relationships that could be exploited for drug development.
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Registered trials
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