4GLW

DNA ligase A in complex with inhibitor

Summary for 4GLW

• Entry DOI: 10.2210/pdb4glw/pdb
• Related: 3BAA 4GLX
• Descriptor: DNA ligase, SULFATE ION, 7-methoxy-6-methylpteridine-2,4-diamine, ... (5 entities in total)
• Functional Keywords: dna ligase a, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 70127.07

Authors

Prade, L.,Lange, R.,Tidten-Luksch, N.,Chambovey, A. (deposition date: 2012-08-15, release date: 2012-10-10, Last modification date: 2024-02-28)

Primary citation

Surivet, J.P.,Lange, R.,Hubschwerlen, C.,Keck, W.,Specklin, J.L.,Ritz, D.,Bur, D.,Locher, H.,Seiler, P.,Strasser, D.S.,Prade, L.,Kohl, C.,Schmitt, C.,Chapoux, G.,Ilhan, E.,Ekambaram, N.,Athanasiou, A.,Knezevic, A.,Sabato, D.,Chambovey, A.,Gaertner, M.,Enderlin, M.,Boehme, M.,Sippel, V.,Wyss, P.
Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity.
Bioorg.Med.Chem.Lett., 22:6705-6711, 2012

PubMed Abstract: A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1 mg/L) and in vivo anti-staphylococcal activity, is presented.

PubMed: 23006603
DOI: 10.1016/j.bmcl.2012.08.094

Experimental method

X-RAY DIFFRACTION (2 Å)