5AGT

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium Tuberculosis that Target Leucyl-tRNA Synthetase.

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.

(2016) Antimicrob Agents Chemother 60: 6271

  • DOI: https://doi.org/10.1128/AAC.01339-16
  • Primary Citation of Related Structures:  
    5AGR, 5AGS, 5AGT

  • 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.


  • Organizational Affiliation

    European Molecular Biology Laboratory, Grenoble, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
LEUCINE--TRNA LIGASE232Mycobacterium tuberculosis H37RvMutation(s): 0 
EC: 6.1.1.4
UniProt
Find proteins for P9WFV1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WFV1 
Go to UniProtKB:  P9WFV1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WFV1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A2H
Query on A2H

Download Ideal Coordinates CCD File 
C [auth A]4-Chloro-3-aminomethyl-7-[ethoxy]-3H-benzo[C][1,2]oxaborol-1-ol modified adenosine
C20 H22 B Cl N6 O9 P
QVHGEDIRODVXDV-RIMGRJFKSA-L
MET
Query on MET

Download Ideal Coordinates CCD File 
B [auth A]METHIONINE
C5 H11 N O2 S
FFEARJCKVFRZRR-BYPYZUCNSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.183 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.83α = 90
b = 61.88β = 90
c = 76.88γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-02
    Type: Initial release
  • Version 1.1: 2016-08-24
    Changes: Database references
  • Version 1.2: 2016-10-05
    Changes: Database references
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description