EMD-13654

Single-particle
2.9 Å
EMD-13654 Deposition: 28/09/2021
Map released: 23/02/2022
Last modified: 17/07/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-13654

DNA polymerase from M. tuberculosis

EMD-13654

Single-particle
2.9 Å
EMD-13654 Deposition: 28/09/2021
Map released: 23/02/2022
Last modified: 17/07/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Mycobacterium tuberculosis, synthetic construct
Sample: DNA polymerase from M. tuberculosis
Fitted models: 7pu7 (Avg. Q-score: 0.555)

Deposition Authors: Borsellini A , Lamers MH
DNA-Dependent Binding of Nargenicin to DnaE1 Inhibits Replication in Mycobacterium tuberculosis.
PUBMED: 35143160
DOI: doi:10.1021/acsinfecdis.1c00643
ISSN: 2373-8227
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 Staphylococcus aureus, revealed that it is a bactericidal genotoxin that induces a DNA damage response in Mycobacterium tuberculosis (Mtb) and inhibits growth by blocking the replicative DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding of nargenicin to Mtb 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 Mtb DnaE1.