5AGJ

Crystal structure of the LeuRS editing domain of Candida albicans in complex with the adduct AN2690-AMP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Analysis of the Resistance Mechanism of a Benzoxaborole Inhibitor Reveals Insight Into the Leucyl-tRNA Synthetase Editing Mechanism.

Zhao, H.Palencia, A.Seiradake, E.Ghaemi, Z.Cusack, S.Luthey-Schulten, Z.Martinis, S.

(2015) ACS Chem Biol 10: 2277

  • DOI: https://doi.org/10.1021/acschembio.5b00291
  • Primary Citation of Related Structures:  
    5AGH, 5AGI, 5AGJ

  • PubMed Abstract: 

    A new class of antimicrobial benzoxaborole compounds was identified as a potent inhibitor of leucyl-tRNA synthetase (LeuRS) and therefore of protein synthesis. In a novel mechanism, AN2690 (5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole) blocks fungal cytoplasmic LeuRS by covalently trapping tRNA(Leu) in the editing site of the enzyme's CP1 domain. However, some resistant mutation sites are located outside of the CP1 hydrolytic editing active site. Thus, their mode of action that undermines drug inhibition was not understood. A combination of X-ray crystallography, molecular dynamics, metadynamics, biochemical experiments, and mutational analysis of a distal benzoxaborole-resistant mutant uncovered a eukaryote-specific tyrosine "switch" that is critical to tRNA-dependent post-transfer editing. The tyrosine "switch" has three states that shift between interactions with a lysine and the 3'-hydroxyl of the tRNA terminus, to inhibit or promote post-transfer editing. The oxaborole's mechanism of action capitalizes upon one of these editing active site states. This tunable editing mechanism in eukaryotic and archaeal LeuRSs is proposed to facilitate precise quality control of aminoacylation fidelity. These mechanistic distinctions could also be capitalized upon for development of the benzoxaboroles as a broad spectrum antibacterial.


  • Organizational Affiliation

    European Molecular Biology Laboratory, Grenoble Outstation and Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, UMI 3265 , 71 Avenue des Martyrs, BP181, 38042 Grenoble Cedex 9, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
POTENTIAL CYTOSOLIC LEUCYL TRNA SYNTHETASE261Candida albicans SC5314Mutation(s): 0 
EC: 6.1.1.4
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ANZ
Query on ANZ

Download Ideal Coordinates CCD File 
B [auth A][(6-AMINO-9H-PURIN-9-YL)-[5-FLUORO-1,3-DIHYDRO-1-HYDROXY-2,1-BENZOXABOROLE]-4'YL]METHYL DIHYDROGEN PHOSPHATE
C17 H17 B F N5 O8 P
ZLSXXTYLUMEAGG-LBTDBDNISA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.181 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.95α = 90
b = 59.26β = 90
c = 97.15γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-01
    Type: Initial release
  • Version 1.1: 2015-07-29
    Changes: Database references
  • Version 1.2: 2015-10-28
    Changes: Database references
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description