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Structural basis for TNA synthesis by an engineered TNA polymerase

Author

Listed:
  • Nicholas Chim

    (Chemistry, and Molecular Biology and Biochemistry University of California)

  • Changhua Shi

    (Chemistry, and Molecular Biology and Biochemistry University of California)

  • Sujay P. Sau

    (Chemistry, and Molecular Biology and Biochemistry University of California)

  • Ali Nikoomanzar

    (Chemistry, and Molecular Biology and Biochemistry University of California)

  • John C. Chaput

    (Chemistry, and Molecular Biology and Biochemistry University of California)

Abstract

Darwinian evolution experiments carried out on xeno-nucleic acid (XNA) polymers require engineered polymerases that can faithfully and efficiently copy genetic information back and forth between DNA and XNA. However, current XNA polymerases function with inferior activity relative to their natural counterparts. Here, we report five X-ray crystal structures that illustrate the pathway by which α-(l)-threofuranosyl nucleic acid (TNA) triphosphates are selected and extended in a template-dependent manner using a laboratory-evolved polymerase known as Kod-RI. Structural comparison of the apo, binary, open and closed ternary, and translocated product detail an ensemble of interactions and conformational changes required to promote TNA synthesis. Close inspection of the active site in the closed ternary structure reveals a sub-optimal binding geometry that explains the slow rate of catalysis. This key piece of information, which is missing for all naturally occurring archaeal DNA polymerases, provides a framework for engineering new TNA polymerase variants.

Suggested Citation

  • Nicholas Chim & Changhua Shi & Sujay P. Sau & Ali Nikoomanzar & John C. Chaput, 2017. "Structural basis for TNA synthesis by an engineered TNA polymerase," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02014-0
    DOI: 10.1038/s41467-017-02014-0
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