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

Gaur, Vineet; Vyas, Rajan; Fowler, Jason D.; Efthimiopoulos, Georgia; Feng, Joy Y.; Suo, Zucai

doi:10.1093/nar/gku709

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

Journal Article · Thu Aug 07 00:00:00 EDT 2014 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gku709· OSTI ID:1625540

Gaur, Vineet ^[1]; Vyas, Rajan ^[2]; Fowler, Jason D. ^[2]; Efthimiopoulos, Georgia ^[2]; Feng, Joy Y. ^[3]; Suo, Zucai ^[2]

The Ohio State Univ., Columbus, OH (United States). Dept. of Chemistry and Biochemistry; DOE/OSTI
The Ohio State Univ., Columbus, OH (United States). Dept. of Chemistry and Biochemistry
Gilead Sciences, Inc., Foster City, CA (United States)

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 strong D-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.

View Accepted Manuscript (DOE)

Research Organization:: The Ohio State University, Columbus, OH (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1625540

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 15 Vol. 42; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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