ArticleProceedings of the National Academy of Sciences of the United States of America2015
Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Molecular and structural basis for replication initiation and strand separation by human mitochondrial DNA polymerase γ.Nucleic acids research · 2026Article
- Structural and single-molecule insights into the core human mitochondrial DNA replisome.The Biochemical journal · 2026Review
- Higher-order structural organization of mitochondrial metabolism.The Journal of biological chemistry · 2026Review
- The POLγ Y951N patient mutation disrupts the switch between DNA synthesis and proofreading, triggering mitochondrial DNA instability.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Antiretroviral-Induced Toxicity in Umbilical Cord Blood-Derived Haematopoietic Stem/Progenitor Cells.Journal of cellular and molecular medicine · 2025Article
- Structural basis for intrinsic strand displacement activity of mitochondrial DNA polymerase.Nature communications · 2025Article
- Sequential requirements for distinct Polθ domains during theta-mediated end joining.Molecular cell · 2024Article
- T-cell immunity against senescence: potential role and perspectives.Frontiers in immunology · 2024Review
- Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity.Nature structural & molecular biology · 2023Article
- Mechanism of strand displacement DNA synthesis by the coordinated activities of human mitochondrial DNA polymerase and SSB.Nucleic acids research · 2023Article
- Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity.Molecules (Basel, Switzerland) · 2023Review
- Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurposing.Drug discovery today · 2022Review
- Mitochondrial and metabolic dysfunction in ageing and age-related diseases.Nature reviews. Endocrinology · 2022Review
- Human Mitochondrial DNA Polymerase Metal Dependent UV Lesion Bypassing Ability.Frontiers in molecular biosciences · 2022Article
- Antivirals for Coexistence with COVID-19: Brief Review for General Physicians.Journal of Korean medical science · 2021Review
- An atomistic model of the coronavirus replication-transcription complex as a hexamer assembled around nsp15.The Journal of biological chemistry · 2021Article
- Photoinduced Photosensitizer-Antibody Conjugates Kill HIV Env-Expressing Cells, Also Inactivating HIV.ACS omega · 2021Article
- A non-radioactive DNA synthesis assay demonstrates that elements of the Sigma 1278b Mip1 mitochondrial DNA polymerase domain and C-terminal extension facilitate robust enzyme activity.Yeast (Chichester, England) · 2021Article
- A case series of emtricitabine-induced pure red cell aplasia.Southern African journal of HIV medicine · 2021Article
- Structure and function relationships in mammalian DNA polymerases.Cellular and molecular life sciences : CMLS · 2020Review
Corrections and comments
- Erratum issued
Authors and funding
8 authors.
Funding
Abstract
Nucleoside analog reverse transcriptase inhibitors (NRTIs) are the essential components of highly active antiretroviral (HAART) therapy targeting HIV reverse transcriptase (RT). NRTI triphosphates (NRTI-TP), the biologically active forms, act as chain terminators of viral DNA synthesis. Unfortunately, NRTIs also inhibit human mitochondrial DNA polymerase (Pol γ), causing unwanted mitochondrial toxicity. Understanding the structural and mechanistic differences between Pol γ and RT in response to NRTIs will provide invaluable insight to aid in designing more effective drugs with lower toxicity. The NRTIs emtricitabine [(-)-2,3'-dideoxy-5-fluoro-3'-thiacytidine, (-)-FTC] and lamivudine, [(-)-2,3'-dideoxy-3'-thiacytidine, (-)-3TC] are both potent RT inhibitors, but Pol γ discriminates against (-)-FTC-TP by two orders of magnitude better than (-)-3TC-TP. Furthermore, although (-)-FTC-TP is only slightly more potent against HIV RT than its enantiomer (+)-FTC-TP, it is discriminated by human Pol γ four orders of magnitude more efficiently than (+)-FTC-TP. As a result, (-)-FTC is a much less toxic NRTI. Here, we present the structural and kinetic basis for this striking difference by identifying the discriminator residues of drug selectivity in both viral and human enzymes responsible for substrate selection and inhibitor specificity. For the first time, to our knowledge, this work illuminates the mechanism of (-)-FTC-TP differential selectivity and provides a structural scaffold for development of novel NRTIs with lower toxicity.
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