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

DOI: 10.1038/s41467-017-00886-w DOI Help

Authors: Soledad Banos-mateos (MRC Laboratory of Molecular Biology) , Anne-marie M. Van 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 Lamers (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 8

State: Published (Approved)
Published: October 2017

Open Access Open Access

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.

Journal Keywords: Drug screening; Pathogens; X-ray crystallography

Subject Areas: Medicine

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 16/10/2017 08:57


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