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5AGR

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

5AGR の概要
エントリーDOI10.2210/pdb5agr/pdb
関連するPDBエントリー5AGS 5AGT
分子名称LEUCINE--TRNA LIGASE, METHIONINE, LEUCINE, ... (6 entities in total)
機能のキーワードligase, 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
タンパク質・核酸の鎖数1
化学式量合計25766.42
構造登録者
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
Cited by
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
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.3 Å)
構造検証レポート
Validation report summary of 5agr
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-07-16に公開中

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