4HWP

Crystal structure of E. coli Threonyl-tRNA synthetase bound to a novel inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Identification of bacteria-selective threonyl-tRNA synthetase substrate inhibitors by structure-based design.

Teng, M.Hilgers, M.T.Cunningham, M.L.Borchardt, A.Locke, J.B.Abraham, S.Haley, G.Kwan, B.P.Hall, C.Hough, G.W.Shaw, K.J.Finn, J.

(2013) J Med Chem 56: 1748-1760

  • DOI: https://doi.org/10.1021/jm301756m
  • Primary Citation of Related Structures:  
    4HWO, 4HWP, 4HWR, 4HWS, 4HWT

  • PubMed Abstract: 

    A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the compounds displayed greatly improved bacterial selectivity. Key residues responsible for potency and bacteria/human ThrRS selectivity have been identified. Antimicrobial activity has been achieved against wild-type Haemophilus influenzae and efflux-deficient mutants of Escherichia coli and Burkholderia thailandensis.


  • Organizational Affiliation

    Medicinal Chemistry, Trius Therapeutics, Inc., 6310 Nancy Ridge Drive, San Diego, California 92121, United States. mteng@triusrx.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Threonine--tRNA ligase
A, B
411Escherichia coli K-12Mutation(s): 0 
Gene Names: thrSb1719JW1709
EC: 6.1.1.3
UniProt
Find proteins for P0A8M3 (Escherichia coli (strain K12))
Explore P0A8M3 
Go to UniProtKB:  P0A8M3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0A8M3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
X16 PDBBind:  4HWP Ki: 17.2 (nM) from 1 assay(s)
BindingDB:  4HWP Ki: 9.3 (nM) from 1 assay(s)
Binding MOAD:  4HWP Ki: 17.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.16α = 90
b = 110.14β = 90
c = 115.45γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-09-18
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations, Refinement description