6POI

Crystal Structure of EcDsbA in complex phenyl ether 25


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 

wwPDB Validation 3D Report Full Report



Literature

The Fragment-Based Development of a Benzofuran Hit as a New Class ofEscherichia coliDsbA Inhibitors.

Duncan, L.F.Wang, G.Ilyichova, O.V.Scanlon, M.J.Heras, B.Abbott, B.M.

(2019) Molecules 24

  • DOI: 10.3390/molecules24203756
  • Structures With Same Primary Citation

  • PubMed Abstract: 
  • A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli ( Ec DsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram ...

    A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli ( Ec DsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening of a library of fragments identified several classes of fragments with affinity to Ec DsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid ( 6 ), was chemically elaborated at several positions around the scaffold. X-ray crystal structures of the elaborated analogues showed binding in the hydrophobic binding groove adjacent to the catalytic disulfide bond of Ec DsbA. Binding affinity was calculated based on NMR studies and compounds 25 and 28 were identified as the highest affinity binders with dissociation constants ( K D ) of 326 ± 25 and 341 ± 57 µM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of Ec DsbA inhibitors.


    Organizational Affiliation

    Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia. B.Abbott@latrobe.edu.au.



Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Thiol:disulfide interchange protein DsbA
A, B
189Escherichia coli K-12Mutation(s): 0 
Gene Names: dsbAdsfppfAb3860JW3832
Find proteins for P0AEG4 (Escherichia coli (strain K12))
Go to UniProtKB:  P0AEG4
Small Molecules
Ligands 2 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
OVS
Query on OVS

Download CCD File 
A
(6-phenoxy-1-benzofuran-3-yl)acetic acid
C16 H12 O4
SLCAFBFROXEZHX-UHFFFAOYSA-N
 Ligand Interaction
CU
Query on CU

Download CCD File 
B
COPPER (II) ION
Cu
JPVYNHNXODAKFH-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.77 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 117.75α = 90
b = 63.67β = 140.96
c = 96.6γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History 

  • Version 1.0: 2019-11-06
    Type: Initial release