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Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ.

Sohl CD, Szymanski MR, Mislak AC, Shumate CK, Amiralaei S, Schinazi RF, Anderson KS, Yin YW
Proc Natl Acad Sci U S A 112 8596-601 (2015)
Related entries: 5c51, 5c52

Cited: 27 times
EuropePMC logo PMID: 26124101

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.

Reviews - 5c53 mentioned but not cited (3)

  1. Translesion and Repair DNA Polymerases: Diverse Structure and Mechanism. Yang W, Gao Y. Annu Rev Biochem 87 239-261 (2018)
  2. Structure and function relationships in mammalian DNA polymerases. Hoitsma NM, Whitaker AM, Schaich MA, Smith MR, Fairlamb MS, Freudenthal BD. Cell Mol Life Sci 77 35-59 (2020)
  3. Targeting Mitochondrial Function with Chemoptogenetics. Romesberg A, Van Houten B. Biomedicines 10 2459 (2022)

Articles - 5c53 mentioned but not cited (4)

  1. Structured States of Disordered Proteins from Genomic Sequences. Toth-Petroczy A, Palmedo P, Ingraham J, Hopf TA, Berger B, Sander C, Marks DS. Cell 167 158-170.e12 (2016)
  2. Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ. Sohl CD, Szymanski MR, Mislak AC, Shumate CK, Amiralaei S, Schinazi RF, Anderson KS, Yin YW. Proc Natl Acad Sci U S A 112 8596-8601 (2015)
  3. 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. Bertoletti N, Chan AH, Schinazi RF, Yin YW, Anderson KS. Protein Sci 28 1664-1675 (2019)
  4. 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. Young MJ, Imperial RJ, Lakhi S, Court DA. Yeast 38 262-275 (2021)


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  1. Mammalian Mitochondria and Aging: An Update. Kauppila TES, Kauppila JHK, Larsson NG. Cell Metab 25 57-71 (2017)
  2. The role of mitochondria in aging. Jang JY, Blum A, Liu J, Finkel T. J Clin Invest 128 3662-3670 (2018)
  3. Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Amorim JA, Coppotelli G, Rolo AP, Palmeira CM, Ross JM, Sinclair DA. Nat Rev Endocrinol 18 243-258 (2022)
  4. Animal Mitochondrial DNA Replication. Ciesielski GL, Oliveira MT, Kaguni LS. Enzymes 39 255-292 (2016)
  5. Mitochondrial DNA degradation: A quality control measure for mitochondrial genome maintenance and stress response. Zhao L. Enzymes 45 311-341 (2019)
  6. Mitochondrial Dysfunction in Aging and Cancer. Moro L. J Clin Med 8 E1983 (2019)
  7. Antivirals for Coexistence with COVID-19: Brief Review for General Physicians. Yoo JH. J Korean Med Sci 36 e298 (2021)
  8. Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity. Park J, Baruch-Torres N, Yin YW. Molecules 28 1796 (2023)
  9. Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurposing. Ruiz FX, Hoang A, Dilmore CR, DeStefano JJ, Arnold E. Drug Discov Today 27 1832-1846 (2022)

Articles citing this publication (11)

  1. An atomistic model of the coronavirus replication-transcription complex as a hexamer assembled around nsp15. Perry JK, Appleby TC, Bilello JP, Feng JY, Schmitz U, Campbell EA. J Biol Chem 297 101218 (2021)
  2. Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance. Hung M, Tokarsky EJ, Lagpacan L, Zhang L, Suo Z, Lansdon EB. Commun Biol 2 469 (2019)
  3. Photoinduced Photosensitizer-Antibody Conjugates Kill HIV Env-Expressing Cells, Also Inactivating HIV. Sadraeian M, da Cruz EF, Boyle RW, Bahou C, Chudasama V, Janini LMR, Diaz RS, Guimarães FEG. ACS Omega 6 16524-16534 (2021)
  4. The Δ133p53 Isoform Reduces Wtp53-induced Stimulation of DNA Pol γ Activity in the Presence and Absence of D4T. Liu K, Zang Y, Guo X, Wei F, Yin J, Pang L, Chen D. Aging Dis 8 228-239 (2017)
  5. Structural basis for the D-stereoselectivity of human DNA polymerase β. Vyas R, Reed AJ, Raper AT, Zahurancik WJ, Wallenmeyer PC, Suo Z. Nucleic Acids Res 45 6228-6237 (2017)
  6. Mechanism of strand displacement DNA synthesis by the coordinated activities of human mitochondrial DNA polymerase and SSB. Plaza-G A I, Lemishko KM, Crespo R, Truong TQ, Kaguni LS, Cao-García FJ, Ciesielski GL, Ibarra B. Nucleic Acids Res 51 1750-1765 (2023)
  7. Networked Communication between Polymerase and Exonuclease Active Sites in Human Mitochondrial DNA Polymerase. Sowers ML, Anderson APP, Wrabl JO, Yin YW. J Am Chem Soc 141 10821-10829 (2019)
  8. Human Mitochondrial DNA Polymerase Metal Dependent UV Lesion Bypassing Ability. Park J, Baruch-Torres N, Iwai S, Herrmann GK, Brieba LG, Yin YW. Front Mol Biosci 9 808036 (2022)
  9. A case series of emtricitabine-induced pure red cell aplasia. Manickchund N, du Plessis C, John MA, Manzini TC, Gosnell BI, Moosa MS. South Afr J HIV Med 22 1271 (2021)
  10. Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity. Park J, Herrmann GK, Mitchell PG, Sherman MB, Yin YW. Nat Struct Mol Biol 30 812-823 (2023)
  11. Active Site Interactions Impact Phosphoryl Transfer during Replication of Damaged and Undamaged DNA by Escherichia coli DNA Polymerase I. Prakasha Gowda AS, Spratt TE. Chem Res Toxicol 30 2033-2043 (2017)


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