4KPE

Novel fluoroquinolones in complex with topoisomerase IV from S. pneumoniae and E-site G-gate

Summary for 4KPE

• Entry DOI: 10.2210/pdb4kpe/pdb
• Related: 2NOV 3FOE 3FOF 3K9F 3KSA 3KSB 3LTN 3RAD 3RAE 3RAF 4KOE 4KPF
• Descriptor: DNA topoisomerase 4 subunit A, DNA topoisomerase 4 subunit B, E-site DNA1, ... (9 entities in total)
• Functional Keywords: protein-dna cleavage complex, isomerase-dna-inhibitor complex, topoisomerase iia, quinolone, achn-245, isomerase/dna/inhibitor
• Biological source: Streptococcus pneumoniae; More
• Total number of polymer chains: 8
• Total formula weight: 185568.15

Authors

Laponogov, I.,Pan, X.-S.,Vesekov, D.A.,Cirz, R.T.,Wagman, A.S.,Moser, H.E.,Fisher, L.M.,Sanderson, M.R. (deposition date: 2013-05-13, release date: 2014-11-26, Last modification date: 2024-10-16)

Primary citation

Laponogov, I.,Pan, X.S.,Veselkov, D.A.,Cirz, R.T.,Wagman, A.,Moser, H.E.,Fisher, L.M.,Sanderson, M.R.
Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones.
Open Biol, 6:-, 2016

PubMed Abstract: As part of a programme of synthesizing and investigating the biological properties of new fluoroquinolone antibacterials and their targeting of topoisomerase IV from Streptococcus pneumoniae, we have solved the X-ray structure of the complexes of two new 7,8-bridged fluoroquinolones (with restricted C7 group rotation favouring tight binding) in complex with the topoisomerase IV from S. pneumoniae and an 18-base-pair DNA binding site-the E-site-found by our DNA mapping studies to bind drug strongly in the presence of topoisomerase IV (Leo et al. 2005 J. Biol. Chem. 280, 14 252-14 263, doi:10.1074/jbc.M500156200). Although the degree of antibiotic resistance towards fluoroquinolones is much lower than that of β-lactams and a range of ribosome-bound antibiotics, there is a pressing need to increase the diversity of members of this successful clinically used class of drugs. The quinolone moiety of the new 7,8-bridged agents ACHN-245 and ACHN-454 binds similarly to that of clinafloxocin, levofloxacin, moxifloxacin and trovofloxacin but the cyclic scaffold offers the possibility of chemical modification to produce interactions with other topoisomerase residues at the active site.

PubMed: 27655731
DOI: 10.1098/rsob.160157

Experimental method

X-RAY DIFFRACTION (3.43 Å)