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

Soledad Baños-Mateos, Anne-Marie M. Roon, Ulla F. Lang, Sarah L. Maslen, J. Mark Skehel and Meindert H. Lamers ()
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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

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00886-w

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