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PDBsum entry 4lp0

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protein ligands links
Isomerase/isomerase inhibitor PDB id
4lp0
Jmol
Contents
Protein chain
192 a.a.
Ligands
1YM
Waters ×107
PDB id:
4lp0
Name: Isomerase/isomerase inhibitor
Title: Crystal structure of a topoisomerase atp inhibitor
Structure: Topoisomerase iv subunit b. Chain: a. Fragment: atpase domain, unp residues 1-226. Engineered: yes
Source: Streptococcus pneumoniae. Organism_taxid: 171101. Strain: atcc baa-255 / r6. Gene: pare, spr0756. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
1.95Å     R-factor:   0.168     R-free:   0.202
Authors: G.S.Basarab,J.I.Manchester,S.Bist,P.A.Boriack-Sjodin,B.Dange R.Illingsworth,M.Uria-Nickelsen,B.A.Sherer,S.Sriram,A.E.Eak
Key ref: G.S.Basarab et al. (2013). Fragment-to-hit-to-lead discovery of a novel pyridylurea scaffold of ATP competitive dual targeting type II topoisomerase inhibiting antibacterial agents. J Med Chem, 56, 8712-8735. PubMed id: 24098982 DOI: 10.1021/jm401208b
Date:
14-Jul-13     Release date:   13-Nov-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q8DQB5  (Q8DQB5_STRR6) -  DNA topoisomerase 4 subunit B
Seq:
Struc:
 
Seq:
Struc:
647 a.a.
192 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.5.99.1.3  - Dna topoisomerase (ATP-hydrolyzing).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP-dependent breakage, passage and rejoining of double-stranded DNA.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     DNA topological change   1 term 
  Biochemical function     DNA binding     3 terms  

 

 
DOI no: 10.1021/jm401208b J Med Chem 56:8712-8735 (2013)
PubMed id: 24098982  
 
 
Fragment-to-hit-to-lead discovery of a novel pyridylurea scaffold of ATP competitive dual targeting type II topoisomerase inhibiting antibacterial agents.
G.S.Basarab, J.I.Manchester, S.Bist, P.A.Boriack-Sjodin, B.Dangel, R.Illingworth, B.A.Sherer, S.Sriram, M.Uria-Nickelsen, A.E.Eakin.
 
  ABSTRACT  
 
The discovery and optimization of a new class of bacterial topoisomerase (DNA gyrase and topoisomerase IV) inhibitors binding in the ATP domain are described. A fragment molecule, 1-ethyl-3-(2-pyridyl)urea, provided sufficiently potent enzyme inhibition (32 μM) to prompt further analogue work. Acids and acid isosteres were incorporated at the 5-pyridyl position of this fragment, bridging to a key asparagine residue, improving enzyme inhibition, and leading to measurable antibacterial activity. A CF3-thiazole substituent at the 4-pyridyl position improved inhibitory potency due to a favorable lipophilic interaction. Promising antibacterial activity was seen versus the Gram-positive pathogens Staphylococcus aureus and Streptococcus pneumoniae and the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis . Precursor metabolite incorporation and mutant analysis studies support the mode-of-action, blockage of DNA synthesis by dual target topoisomerase inhibition. Compound 35 was efficacious in a mouse S. aureus disease model, where a 4.5-log reduction in colony forming units versus control was demonstrated.