4K48

Structure of the Streptococcus pneumoniae leucyl-tRNA synthetase editing domain

4K48 の概要

• エントリーDOI: 10.2210/pdb4k48/pdb
• 関連するPDBエントリー: 4K47
• 分子名称: Leucine--tRNA ligase (2 entities in total)
• 機能のキーワード: leucyl-trna synthetase, benzoxaboroles, antibacterial, ligase
• 由来する生物種: Streptococcus pneumoniae
• 細胞内の位置: Cytoplasm (By similarity): B8ZKS5
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21091.47

構造登録者

Hu, Q.H.,Liu, R.J.,Fang, Z.P.,Zhang, J.,Ding, Y.Y.,Tan, M.,Wang, M.,Pan, W.,Zhou, H.C.,Wang, E.D. (登録日: 2013-04-12, 公開日: 2013-09-04, 最終更新日: 2023-11-08)

主引用文献

Hu, Q.H.,Liu, R.J.,Fang, Z.P.,Zhang, J.,Ding, Y.Y.,Tan, M.,Wang, M.,Pan, W.,Zhou, H.C.,Wang, E.D.
Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase
Sci Rep, 3:2475-2475, 2013

PubMed Abstract: Streptococcus pneumoniae causes bacterial pneumonia with high mortality and morbidity. The emergency of multidrug-resistant bacteria threatens the treatment of the disease. Leucyl-tRNA synthetase (LeuRS) plays an essential role in cellular translation and is an attractive drug target for antimicrobial development. Here we report the compound ZCL039, a benzoxaborole-based derivative of AN2690, as a potent anti-pneumococcal agent that inhibits S. pneumoniae LeuRS (SpLeuRS) activity. We show using kinetic, biochemical analyses combined with the crystal structure of ZCL039-AMP in complex with the separated SpLeuRS editing domain, that ZCL039 binds to the LeuRS editing active site which requires the presence of tRNA(Leu), and employs an uncompetitive inhibition mechanism. Further docking models establish that ZCL039 clashes with the eukaryal/archaeal specific insertion I4ae helix within editing domains. These findings demonstrate the potential of benzoxaboroles as effective LeuRS inhibitors for pneumococcus infection therapy, and provide future structure-guided drug design and optimization.

PubMed: 23959225
DOI: 10.1038/srep02475

実験手法

X-RAY DIFFRACTION (2.49 Å)