4DFU

Inhibition of an antibiotic resistance enzyme: crystal structure of aminoglycoside phosphotransferase APH(2")-ID/APH(2")-IVA in complex with kanamycin inhibited with quercetin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.98 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

A small molecule discrimination map of the antibiotic resistance kinome.

Shakya, T.Stogios, P.J.Waglechner, N.Evdokimova, E.Ejim, L.Blanchard, J.E.McArthur, A.G.Savchenko, A.Wright, G.D.

(2011) Chem Biol 18: 1591-1601

  • DOI: https://doi.org/10.1016/j.chembiol.2011.10.018
  • Primary Citation of Related Structures:  
    4DBX, 4DE4, 4DFB, 4DFU

  • PubMed Abstract: 

    Kinase-mediated resistance to antibiotics is a significant clinical challenge. These enzymes share a common protein fold characteristic of Ser/Thr/Tyr protein kinases. We screened 14 antibiotic resistance kinases against 80 chemically diverse protein kinase inhibitors to map resistance kinase chemical space. The screens identified molecules with both broad and narrow inhibition profiles, proving that protein kinase inhibitors offer privileged chemical matter with the potential to block antibiotic resistance. One example is the flavonol quercetin, which inhibited a number of resistance kinases in vitro and in vivo. This activity was rationalized by determination of the crystal structure of the aminoglycoside kinase APH(2″)-IVa in complex with quercetin and its antibiotic substrate kanamycin. Our data demonstrate that protein kinase inhibitors offer chemical scaffolds that can block antibiotic resistance, providing leads for co-drug design.


  • Organizational Affiliation

    M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 3Z5, Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
APH(2")-Id
A, B
322Enterococcus casseliflavusMutation(s): 0 
Gene Names: APH(2")-Id
UniProt
Find proteins for O68183 (Enterococcus casseliflavus)
Explore O68183 
Go to UniProtKB:  O68183
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO68183
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
MSE
Query on MSE
A, B
L-PEPTIDE LINKINGC5 H11 N O2 SeMET
Binding Affinity Annotations 
IDSourceBinding Affinity
QUE PDBBind:  4DFU Ki: 2.51e+4 (nM) from 1 assay(s)
Binding MOAD:  4DFU Ki: 2.51e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.141α = 90
b = 101.814β = 96.86
c = 70.249γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-08
    Type: Initial release
  • Version 1.1: 2012-02-22
    Changes: Structure summary
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-12-06
    Changes: Data collection
  • Version 1.4: 2024-03-13
    Changes: Source and taxonomy