5AGS

Crystal structure of the LeuRS editing domain of Mycobacterium tuberculosis in complex with the adduct 3-(Aminomethyl)-4-bromo-7-ethoxybenzo[c][1,2]oxaborol-1(3H)-ol-AMP

5AGS の概要

• エントリーDOI: 10.2210/pdb5ags/pdb
• 関連するPDBエントリー: 5AGR 5AGT
• 分子名称: LEUCYL-TRNA SYNTHETASE, METHIONINE, 3-(AMINOMETHYL)-4-BROMO-7-ETHOXYBENZO[C][1,2]OXABOROL-1(3H)-OL-MODIFIED ADENOSINE, ... (4 entities in total)
• 機能のキーワード: ligase, m.tuberculosis, leucine-trna ligase activity, atp + l-leucine + trna(leu) gives amp + diphosphate + l-leucyl- trna(leu) aminoacyl-trna editing activity, aminoacyl-trna synthetase, protein biosynthesis, novel boron inhibitors of leurs
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• 細胞内の位置: Cytoplasm : P9WFV1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25655.10

構造登録者

Palencia, A.,Li, X.,Alley, M.R.K.,Ding, C.,Easom, E.E.,Hernandez, V.,Meewan, M.,Mohan, M.,Rock, F.L.,Franzblau, S.G.,Wang, Y.,Lenaerts, A.J.,Parish, T.,Cooper, C.B.,Waters, M.G.,Ma, Z.,Mendoza, A.,Barros, D.,Cusack, S.,Plattner, J.J. (登録日: 2015-02-03, 公開日: 2016-03-09, 最終更新日: 2024-01-10)

主引用文献

Palencia, A.,Li, X.,Bu, W.,Choi, W.,Ding, C.Z.,Easom, E.E.,Feng, L.,Hernandez, V.,Houston, P.,Liu, L.,Meewan, M.,Mohan, M.,Rock, F.L.,Sexton, H.,Zhang, S.,Zhou, Y.,Wan, B.,Wang, Y.,Franzblau, S.G.,Woolhiser, L.,Gruppo, V.,Lenaerts, A.J.,O'Malley, T.,Parish, T.,Cooper, C.B.,Waters, M.G.,Ma, Z.,Ioerger, T.R.,Sacchettini, J.C.,Rullas, J.,Angulo-Barturen, I.,Perez-Herran, E.,Mendoza, A.,Barros, D.,Cusack, S.,Plattner, J.J.,Alley, M.R.K.
Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium Tuberculosis that Target Leucyl-tRNA Synthetase.
Antimicrob.Agents Chemother., 60:6271-, 2016

PubMed Abstract: The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.

PubMed: 27503647
DOI: 10.1128/AAC.01339-16

実験手法

X-RAY DIFFRACTION (1.47 Å)