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Structural and kinetic insights into binding and incorporation of L-nucleotide analogs by a Y-family DNA polymerase.

Gaur V, Vyas R, Fowler JD, Efthimiopoulos G, Feng JY, Suo Z
Nucleic Acids Res 42 9984-95 (2014)
Related entries: 4qw8, 4qw9, 4qwa, 4qwb, 4qwc, 4qwd

Cited: 13 times
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Abstract

Considering that all natural nucleotides (D-dNTPs) and the building blocks (D-dNMPs) of DNA chains possess D-stereochemistry, DNA polymerases and reverse transcriptases (RTs) likely possess strongD-stereoselectivity by preferably binding and incorporating D-dNTPs over unnatural L-dNTPs during DNA synthesis. Surprisingly, a structural basis for the discrimination against L-dNTPs by DNA polymerases or RTs has not been established although L-deoxycytidine analogs (lamivudine and emtricitabine) and L-thymidine (telbivudine) have been widely used as antiviral drugs for years. Here we report seven high-resolution ternary crystal structures of a prototype Y-family DNA polymerase, DNA, and D-dCTP, D-dCDP, L-dCDP, or the diphosphates and triphosphates of lamivudine and emtricitabine. These structures reveal that relative to D-dCTP, each of these L-nucleotides has its sugar ring rotated by 180° with an unusual O4'-endo sugar puckering and exhibits multiple triphosphate-binding conformations within the active site of the polymerase. Such rare binding modes significantly decrease the incorporation rates and efficiencies of these L-nucleotides catalyzed by the polymerase.

Articles - 4qwe mentioned but not cited (1)

  1. Structural and kinetic insights into binding and incorporation of L-nucleotide analogs by a Y-family DNA polymerase. Gaur V, Vyas R, Fowler JD, Efthimiopoulos G, Feng JY, Suo Z. Nucleic Acids Res 42 9984-9995 (2014)


Reviews citing this publication (2)

  1. Ribonucleotides in bacterial DNA. Schroeder JW, Randall JR, Matthews LA, Simmons LA. Crit Rev Biochem Mol Biol 50 181-193 (2015)
  2. 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 (10)

  1. A polar filter in DNA polymerases prevents ribonucleotide incorporation. Johnson MK, Kottur J, Nair DT. Nucleic Acids Res 47 10693-10705 (2019)
  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. Mechanistic Basis for the Bypass of a Bulky DNA Adduct Catalyzed by a Y-Family DNA Polymerase. Vyas R, Efthimiopoulos G, Tokarsky EJ, Malik CK, Basu AK, Suo Z. J Am Chem Soc 137 12131-12142 (2015)
  4. Significant impact of divalent metal ions on the fidelity, sugar selectivity, and drug incorporation efficiency of human PrimPol. Tokarsky EJ, Wallenmeyer PC, Phi KK, Suo Z. DNA Repair (Amst) 49 51-59 (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. Backbone assignment of the binary complex of the full length Sulfolobus solfataricus DNA polymerase IV and DNA. Lee E, Fowler JD, Suo Z, Wu Z. Biomol NMR Assign 11 39-43 (2017)
  7. Compatibility and Fidelity of Mirror-Image Thymidine in Transcription Events by T7 RNA Polymerase. Liu Q, Ke Y, Kan Y, Tang X, Li X, He Y, Wu L. Mol Ther Nucleic Acids 21 604-613 (2020)
  8. Advances in Structural and Single-Molecule Methods for Investigating DNA Lesion Bypass and Repair Polymerases. Raper AT, Reed AJ, Gadkari VV, Suo Z. Chem Res Toxicol 30 260-269 (2017)
  9. Computational Evaluation of Nucleotide Insertion Opposite Expanded and Widened DNA by the Translesion Synthesis Polymerase Dpo4. Albrecht L, Wilson KA, Wetmore SD. Molecules 21 E822 (2016)
  10. Replicative bypass studies of l-deoxyribonucleosides in Vitro and in E. coli cell. Kan Y, Jin Z, Ke Y, Lin D, Yan L, Wu L, He Y. Sci Rep 12 21183 (2022)


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