3ZJV

Ternary complex of E .coli leucyl-tRNA synthetase, tRNA(Leu) and the benzoxaborole AN3213 in the editing conformation

3ZJV の概要

• エントリーDOI: 10.2210/pdb3zjv/pdb
• 関連するPDBエントリー: 3ZJT 3ZJU
• 分子名称: LEUCINE--TRNA LIGASE, TRNALEU5 UAA ISOACCEPTOR (3 entities in total)
• 機能のキーワード: ligase-rna complex, ligase, protein biosynthesis, class i aminoacyl-trna synthetase, aminoacyl trna synthetase, atp binding, editing synthetase, ligase/rna
• 由来する生物種: ESCHERICHIA COLI; 詳細
• 細胞内の位置: Cytoplasm: P07813
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 127786.71

構造登録者

Cusack, S.,Palencia, A.,Crepin, T.,Hernandez, V.,Akama, T.,Baker, S.J.,Bu, W.,Feng, L.,Freund, Y.R.,Liu, L.,Meewan, M.,Mohan, M.,Mao, W.,Rock, F.L.,Sexton, H.,Sheoran, A.,Zhang, Y.,Zhang, Y.,Zhou, Y.,Nieman, J.A.,Anugula, M.R.,Keramane, E.M.,Savariraj, K.,Reddy, D.S.,Sharma, R.,Subedi, R.,Singh, R.,OLeary, A.,Simon, N.L.,DeMarsh, P.L.,Mushtaq, S.,Warner, M.,Livermore, D.M.,Alley, M.R.K.,Plattner, J.J. (登録日: 2013-01-18, 公開日: 2013-04-17, 最終更新日: 2023-12-20)

主引用文献

Hernandez, V.,Crepin, T.,Palencia, A.,Cusack, S.,Akama, T.,Baker, S.J.,Bu, W.,Feng, L.,Freund, Y.R.,Liu, L.,Meewan, M.,Mohan, M.,Mao, W.,Rock, F.L.,Sexton, H.,Sheoran, A.,Zhang, Y.,Zhang, Y.,Zhou, Y.,Nieman, J.A.,Anugula, M.R.,Keramane, E.M.,Savariraj, K.,Reddy, D.S.,Sharma, R.,Subedi, R.,Singh, R.,O'Leary, A.,Simon, N.L.,De Marsh, P.L.,Mushtaq, S.,Warner, M.,Livermore, D.M.,Alley, M.R.K.,Plattner, J.J.
Discovery of a Novel Class of Boron-Based Antibacterials with Activity Against Gram-Negative Bacteria.
Antimicrob.Agents Chemother., 57:1394-, 2013

PubMed Abstract: Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.

PubMed: 23295920
DOI: 10.1128/AAC.02058-12

実験手法

X-RAY DIFFRACTION (2.31 Å)