2XYU

Crystal structure of EphA4 kinase domain in complex with VUF 12058


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.12 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.192 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Fragment Based Lead Discovery of Small Molecule Inhibitors for the Epha4 Receptor Tyrosine Kinase.

Van Linden, O.P.Farenc, C.J.A.Zoutman, W.H.Hameetman, L.Wijtmans, M.Leurs, R.Tensen, C.P.Siegal, G.De Esch, I.J.

(2012) Eur J Med Chem 47: 493

  • DOI: https://doi.org/10.1016/j.ejmech.2011.11.020
  • Primary Citation of Related Structures:  
    2XYU

  • PubMed Abstract: 

    The in silico identification, optimization and crystallographic characterization of a 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-1-amine scaffold as an inhibitor for the EPHA4 receptor tyrosine kinase is described. A database containing commercially available compounds was subjected to an in silico screening procedure which was focused on finding novel, EPHA4 hinge binding fragments. This resulted in the identification of 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-1-amine derivatives as EPHA4 inhibitors. Hit exploration yielded a compound with 2 μM (IC(50)) affinity for the EPHA4 receptor tyrosine kinase domain. Soaking experiments into a crystal of the EPHA4 kinase domain gave a 2.11Å X-ray structure of the EPHA4 - inhibitor complex, which confirmed the binding mode of the scaffold as proposed by the initial in silico work. The results underscore the strength of fragment based in silico screening as a tool for the discovery of novel lead compounds as small molecule kinase inhibitors.


  • Organizational Affiliation

    Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
EPHRIN TYPE-A RECEPTOR 4,285Mus musculusMutation(s): 0 
EC: 2.7.10.1
UniProt
Find proteins for Q03137 (Mus musculus)
Explore Q03137 
Go to UniProtKB:  Q03137
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ03137
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
Q9G PDBBind:  2XYU IC50: 4500 (nM) from 1 assay(s)
BindingDB:  2XYU IC50: 4500 (nM) from 1 assay(s)
Binding MOAD:  2XYU IC50: 4500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.12 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.544α = 90
b = 91.545β = 90
c = 97.959γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-30
    Type: Initial release
  • Version 1.1: 2011-12-28
    Changes: Other
  • Version 1.2: 2012-01-25
    Changes: Other
  • Version 1.3: 2012-02-01
    Changes: Other
  • Version 1.4: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description