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

Summary for 5AGR

• Entry DOI: 10.2210/pdb5agr/pdb
• Related: 5AGS 5AGT
• Descriptor: LEUCINE--TRNA LIGASE, METHIONINE, LEUCINE, ... (6 entities in total)
• Functional Keywords: 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
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 1
• Total formula weight: 25766.42

Authors

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. (deposition date: 2015-02-03, release date: 2016-03-02, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.3 Å)