4LH7

Crystal structure of a LigA inhibitor

4LH7 の概要

• エントリーDOI: 10.2210/pdb4lh7/pdb
• 関連するPDBエントリー: 4LH6
• 分子名称: DNA ligase, 4-aminothieno[3,2-c]pyridine-2,7-dicarboxamide, BETA-NICOTINAMIDE RIBOSE MONOPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: protein-inhibitor complex, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Enterococcus faecalis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37479.88

構造登録者

Boriack-Sjodin, P.A.,Prince, D.B. (登録日: 2013-06-30, 公開日: 2013-12-25, 最終更新日: 2024-02-28)

主引用文献

Murphy-Benenato, K.,Wang, H.,McGuire, H.M.,Davis, H.E.,Gao, N.,Prince, D.B.,Jahic, H.,Stokes, S.S.,Boriack-Sjodin, P.A.
Identification through structure-based methods of a bacterial NAD(+)-dependent DNA ligase inhibitor that avoids known resistance mutations.
Bioorg.Med.Chem.Lett., 24:360-366, 2014

PubMed Abstract: In an attempt to identify novel inhibitors of NAD(+)-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes.

PubMed: 24287382
DOI: 10.1016/j.bmcl.2013.11.007

実験手法

X-RAY DIFFRACTION (1.9 Å)