9QRL

DNA polymerase with inhibitor #2

This is a non-PDB format compatible entry.

Summary for 9QRL

• Entry DOI: 10.2210/pdb9qrl/pdb
• Related: 9QPC
• EMDB information: 53319
• Descriptor: DNA polymerase III PolC-type, DNA (5'-D(P*TP*AP*A)-3'), DNA (5'-D(P*GP*GP*TP*GP*CP*GP*CP*AP*T)-3'), ... (8 entities in total)
• Functional Keywords: dna polymerase, inhibitor complex, dna binding protein
• Biological source: Enterococcus faecium; More
• Total number of polymer chains: 4
• Total formula weight: 191118.66

Authors

Lamers, M.H.,Urem, M.,Smits, W.K. (deposition date: 2025-04-03, release date: 2025-09-24, Last modification date: 2026-04-08)

Primary citation

Urem, M.,Friggen, A.H.,Musch, N.,Silverman, M.H.,Swain, C.J.,Barbachyn, M.R.,Mortin, L.I.,Yu, X.,DeLuccia, R.J.,Lamers, M.H.,Smits, W.K.
A unique inhibitor conformation selectively targets the DNA polymerase PolC of Gram-positive priority pathogens.
Nat Commun, 16:9784-9784, 2025

PubMed Abstract: Infections with antimicrobial resistant pathogens are a major threat to human health. Inhibitors of the replicative polymerase PolC are a promising novel class of antimicrobials against Gram-positive pathogens, but the structural basis for their activity remains unknown. The first-in-class PolC-targeting antimicrobial, ibezapolstat, is a guanine analogue in late-stage clinical development for the treatment of Clostridioides difficile infections, and related inhibitors are being developed for systemic treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Here, we present the cryo-electron microscopy structures of Enterococcus faecium PolC bound to DNA and in complex with ibezapolstat or the previously-undescribed inhibitor ACX-801. Both inhibitors form base-pairing interactions with the DNA in the active site, thereby competing with incoming dGTP nucleotides. We identify a crucial susceptibility determinant in PolC that is conserved in other organisms, such as C. difficile. This is explained by an unusual non-planar conformation of the inhibitors that induce a binding pocket in PolC. By combining structural, biochemical, bioinformatic and genetic analyses, this work lays the foundation for the rational development of an innovative class of antimicrobials against Gram-positive priority pathogens.

PubMed: 41198680
DOI: 10.1038/s41467-025-65324-8

Experimental method

ELECTRON MICROSCOPY (3.2 Å)