7PU7

DNA polymerase from M. tuberculosis

Summary for 7PU7

• Entry DOI: 10.2210/pdb7pu7/pdb
• EMDB information: 13654
• Descriptor: DNA polymerase III subunit alpha, Template, primer, ... (6 entities in total)
• Functional Keywords: inhibitor, dna polymerase, replication
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 3
• Total formula weight: 140334.19

Authors

Borsellini, A.,Lamers, M.H. (deposition date: 2021-09-28, release date: 2022-02-23, Last modification date: 2024-07-17)

Primary citation

Chengalroyen, M.D.,Mason, M.K.,Borsellini, A.,Tassoni, R.,Abrahams, G.L.,Lynch, S.,Ahn, Y.M.,Ambler, J.,Young, K.,Crowley, B.M.,Olsen, D.B.,Warner, D.F.,Barry Iii, C.E.,Boshoff, H.I.M.,Lamers, M.H.,Mizrahi, V.
DNA-Dependent Binding of Nargenicin to DnaE1 Inhibits Replication in Mycobacterium tuberculosis.
Acs Infect Dis., 8:612-625, 2022

PubMed Abstract: Natural products provide a rich source of potential antimicrobials for treating infectious diseases for which drug resistance has emerged. Foremost among these diseases is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of , revealed that it is a bactericidal genotoxin that induces a DNA damage response in () and inhibits growth by blocking the replicative DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding of nargenicin to DnaE1 requires the DNA substrate such that nargenicin is wedged between the terminal base pair and the polymerase and occupies the position of both the incoming nucleotide and templating base. Comparative analysis across three bacterial species suggests that the activity of nargenicin is partly attributable to the DNA binding affinity of the replicative polymerase. This work has laid the foundation for target-led drug discovery efforts focused on DnaE1.

PubMed: 35143160
DOI: 10.1021/acsinfecdis.1c00643

Experimental method

ELECTRON MICROSCOPY (2.9 Å)