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High-fidelity DNA replication in Mycobacterium tuberculosis relies on a trinuclear zinc center

Author

Listed:
  • Soledad Baños-Mateos

    (MRC Laboratory of Molecular Biology)

  • Anne-Marie M. Roon

    (MRC Laboratory of Molecular Biology)

  • Ulla F. Lang

    (MRC Laboratory of Molecular Biology)

  • Sarah L. Maslen

    (MRC Laboratory of Molecular Biology)

  • J. Mark Skehel

    (MRC Laboratory of Molecular Biology)

  • Meindert H. Lamers

    (MRC Laboratory of Molecular Biology)

Abstract

High-fidelity DNA replication depends on a proofreading 3′–5′ exonuclease that is associated with the replicative DNA polymerase. The replicative DNA polymerase DnaE1 from the major pathogen Mycobacterium tuberculosis (Mtb) uses its intrinsic PHP-exonuclease that is distinct from the canonical DEDD exonucleases found in the Escherichia coli and eukaryotic replisomes. The mechanism of the PHP-exonuclease is not known. Here, we present the crystal structure of the Mtb DnaE1 polymerase. The PHP-exonuclease has a trinuclear zinc center, coordinated by nine conserved residues. Cryo-EM analysis reveals the entry path of the primer strand in the PHP-exonuclease active site. Furthermore, the PHP-exonuclease shows a striking similarity to E. coli endonuclease IV, which provides clues regarding the mechanism of action. Altogether, this work provides important insights into the PHP-exonuclease and reveals unique properties that make it an attractive target for novel anti-mycobacterial drugs.

Suggested Citation

  • Soledad Baños-Mateos & Anne-Marie M. Roon & Ulla F. Lang & Sarah L. Maslen & J. Mark Skehel & Meindert H. Lamers, 2017. "High-fidelity DNA replication in Mycobacterium tuberculosis relies on a trinuclear zinc center," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00886-w
    DOI: 10.1038/s41467-017-00886-w
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