4EMV

Crystal structure of a topoisomerase ATP inhibitor

Summary for 4EMV

• Entry DOI: 10.2210/pdb4emv/pdb
• Related: 4EM7
• Descriptor: DNA topoisomerase IV, B subunit, 5-{2-(ethylcarbamoyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}pyridine-3-carboxylic acid (3 entities in total)
• Functional Keywords: protein-inhibitor complex, atp binding, structure-based drug design, antimicrobial, virtual screen, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Streptococcus pneumoniae GA47373
• Total number of polymer chains: 1
• Total formula weight: 25045.09

Authors

Boriack-Sjodin, P.A.,Manchester, J.,Hull, K. (deposition date: 2012-04-12, release date: 2012-08-01, Last modification date: 2024-02-28)

Primary citation

Manchester, J.I.,Dussault, D.D.,Rose, J.A.,Boriack-Sjodin, P.A.,Uria-Nickelsen, M.,Ioannidis, G.,Bist, S.,Fleming, P.,Hull, K.G.
Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV.
Bioorg.Med.Chem.Lett., 22:5150-5156, 2012

PubMed Abstract: We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and physical property optimization. Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56 μM. These compounds simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections.

PubMed: 22814212
DOI: 10.1016/j.bmcl.2012.05.128

Experimental method

X-RAY DIFFRACTION (1.7 Å)