8QMB
Nucleant-assisted 2.0 A resolution structure of the Streptococcus pneumoniae topoisomerase IV-V18mer DNA complex with the novel fluoroquinolone Delafloxacin
Summary for 8QMB
| Entry DOI | 10.2210/pdb8qmb/pdb |
| Related | 8C41 |
| Descriptor | DNA topoisomerase 4 subunit B,DNA topoisomerase 4 subunit A, ACETATE ION, FORMIC ACID, ... (13 entities in total) |
| Functional Keywords | protein-dna cleavage complex, topoisomerase iia, delafloxacin, topoisomerase iv-dna-antibiotic complex, isomerase, pegylated graphene |
| Biological source | Streptococcus pneumoniae More |
| Total number of polymer chains | 6 |
| Total formula weight | 181444.30 |
| Authors | Najmudin, S.,Pan, X.S.,Wang, B.,Chayen, N.E.,Fisher, L.M.,Sanderson, M.R. (deposition date: 2023-09-21, release date: 2024-10-02, Last modification date: 2025-07-23) |
| Primary citation | Najmudin, S.,Pan, X.S.,Wang, B.,Govada, L.,Chayen, N.E.,Rubio, N.,Shaffer, M.S.P.,Rzepa, H.S.,Fisher, L.M.,Sanderson, M.R. Structural basis of topoisomerase targeting by delafloxacin. Nat Commun, 16:5829-5829, 2025 Cited by PubMed Abstract: Delafloxacin is a potent anionic fluoroquinolone approved for the treatment of respiratory infections that acts by trapping the DNA cleavage complexes of bacterial topoisomerase IV and gyrase. Its N-1-pyridinyl-, C-7-azetidinyl- and C-8-chlorine substituents confer enhanced antibiotic activity against bacteria resistant to other fluoroquinolones, but its mode of action is unclear. Here we present the X-ray crystal structures of a delafloxacin-DNA cleavage complex obtained by co-crystallization with Streptococcus pneumoniae topo IV using a graphene nucleant and solved at 2.0 and 2.4 Å resolution. The two Mg-chelated delafloxacin molecules intercalated at the DNA cleavage site are bound in an unusual conformation involving interacting out-of-plane N-1-aromatic- and C-8-chlorine- substituents. The unprecedented resolution allows comprehensive imaging of water-metal ion links integrating enzyme and DNA through drug-bound and active-site Mg ions plus the discovery of enzyme-bound K ions. Our studies on delafloxacin action suggest that intrinsic target affinity contributes to its activity against quinolone-resistant bacteria. PubMed: 40595483DOI: 10.1038/s41467-025-60688-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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