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

Citation:
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.
PDB ID: 5AGSDownload
MMDB ID: 137217
PDB Deposition Date: 2015/2/3
Updated in MMDB: 2016/10
Experimental Method:
x-ray diffraction
Resolution: 1.47  Å
Source Organism:
Similar Structures:
Biological Unit for 5AGS: monomeric; determined by author and by software (PISA)
Molecular Components in 5AGS
Label Count Molecule
Protein (1 molecule)
1
Leucyl-trna Synthetase(Gene symbol: leuS)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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