8QMC

High resolution structure of the Streptococcus pneumoniae topoisomerase IV-complex with the V-site 18mer dsDNA and novel fluoroquinolone Delafloxacin

8QMC の概要

• エントリーDOI: 10.2210/pdb8qmc/pdb
• 関連するPDBエントリー: 8C41
• 分子名称: DNA topoisomerase (ATP-hydrolyzing),DNA topoisomerase 4 subunit A, (4S)-2-METHYL-2,4-PENTANEDIOL, delafloxacin, ... (12 entities in total)
• 機能のキーワード: protein-dna cleavage complex, topoisomerase iia, delafloxacin, topoisomerase iv-dna-antibiotic complex, isomerase
• 由来する生物種: Streptococcus pneumoniae; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 180905.76

構造登録者

Najmudin, S.,Pan, X.S.,Wang, B.,Chayen, N.E.,Fisher, L.M.,Sanderson, M.R. (登録日: 2023-09-21, 公開日: 2024-10-02, 最終更新日: 2025-07-23)

主引用文献

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

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: 40595483
DOI: 10.1038/s41467-025-60688-3

実験手法

X-RAY DIFFRACTION (2.402 Å)