ArticleProceedings of the National Academy of Sciences of the United States of America2019
Spatial domain organization in the HIV-1 reverse transcriptase p66 homodimer precursor probed by double electron-electron resonance EPR.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 21 citations in OpenAlex.
- Large-scale protein conformational transitions revealed by weighted ensemble simulations and EPR.Chemical science · 2026Article
- Dimerization propensity of the βProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Interplay between protease and reverse transcriptase dimerization in a model HIV-1 polyprotein.Protein science : a publication of the Protein Society · 2024Article
- Xplor-NIH: Better parameters and protocols for NMR protein structure determination.Protein science : a publication of the Protein Society · 2024Article
- Direct observation of negative cooperativity in a detoxification enzyme at the atomic level by Electron Paramagnetic Resonance spectroscopy and simulation.Protein science : a publication of the Protein Society · 2023Article
- Quantitative analysis of sterol-modulated monomer-dimer equilibrium of the βProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Quantitative Agreement between Conformational Substates of Holo Calcium-Loaded Calmodulin Detected by Double Electron-Electron Resonance EPR and Predicted by Molecular Dynamics Simulations.Journal of the American Chemical Society · 2022Article
- Human endogenous retrovirus-K (HERV-K) reverse transcriptase (RT) structure and biochemistry reveals remarkable similarities to HIV-1 RT and opportunities for HERV-K-specific inhibition.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Time-resolved DEER EPR and solid-state NMR afford kinetic and structural elucidation of substrate binding to CaProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Reconstruction of Coupled Intra- and Interdomain Protein Motion from Nuclear and Electron Magnetic Resonance.Journal of the American Chemical Society · 2021Article
- Large Multidomain Protein NMR: HIV-1 Reverse Transcriptase Precursor in Solution.International journal of molecular sciences · 2020Review
- Orientation and dynamics of CuPhysical chemistry chemical physics : PCCP · 2020Article
- Probing the Interaction between HIV-1 Protease and the Homodimeric p66/p66' Reverse Transcriptase Precursor by Double Electron-Electron Resonance EPR Spectroscopy.Chembiochem : a European journal of chemical biology · 2020Article
- Submillisecond Freezing Permits Cryoprotectant-Free EPR Double Electron-Electron Resonance Spectroscopy.Chemphyschem : a European journal of chemical physics and physical chemistry · 2020Article
- Evolving understanding of HIV-1 reverse transcriptase structure, function, inhibition, and resistance.Current opinion in structural biology · 2020Review
- An asymmetry that leads to activity.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
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3 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
HIV type I (HIV-1) reverse transcriptase (RT) catalyzes the conversion of viral RNA into DNA, initiating the chain of events leading to integration of proviral DNA into the host genome. RT is expressed as a single polypeptide chain within the Gag-Pol polyprotein, and either prior to or following excision by HIV-1 protease forms a 66 kDa chain (p66) homodimer precursor. Further proteolytic attack by HIV-1 protease cleaves the ribonuclease H (RNase H) domain of a single subunit to yield the mature p66/p51 heterodimer. Here, we probe the spatial domain organization within the p66 homodimer using pulsed Q-band double electron-electron resonance (DEER) EPR spectroscopy to measure a large number of intra- and intersubunit distances between spin labels attached to surface-engineered cysteines. The DEER-derived distances are fully consistent with the structural subunit asymmetry found in the mature p66/p51 heterodimer in which catalytic activity resides in the p66 subunit, while the p51 subunit purely serves as a structural scaffold. Furthermore, the p66 homodimer precursor undergoes a conformational change involving the thumb, palm, and finger domains in one of the subunits (corresponding to the p66 subunit in the mature p66/p51 heterodimer) from a closed to a partially open state upon addition of a nonnucleoside inhibitor. The relative orientation of the domains was modeled by simulated annealing driven by the DEER-derived distances. Finally, the RNase H domain that is cleaved to generate p51 in the mature p66/p51 heterodimer is present in 2 major conformers. One conformer is fully solvent accessible thereby accounting for the observation that only a single subunit of the p66 homodimer precursor is susceptible to HIV-1 protease.
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