4UXQ

FGFR4 in complex with Ponatinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.205 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Insights Into Fgfr Kinase Isoform Selectivity: Diverse Binding Modes of Azd4547 and Ponatinib in Complex with Fgfr1 and Fgfr4

Tucker, J.A.Klein, T.Breed, J.Breeze, A.L.Overman, R.Phillips, C.Norman, R.A.

(2014) Structure 22: 1764

  • DOI: https://doi.org/10.1016/j.str.2014.09.019
  • Primary Citation of Related Structures:  
    4UXQ, 4V01, 4V04, 4V05

  • PubMed Abstract: 

    The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases has been implicated in a wide variety of cancers. Despite a high level of sequence homology in the ATP-binding site, the majority of reported inhibitors are selective for the FGFR1-3 isoforms and display much reduced potency toward FGFR4, an exception being the Bcr-Abl inhibitor ponatinib. Here we present the crystal structure of the FGFR4 kinase domain and show that both FGFR1 and FGFR4 kinase domains in complex with ponatinib adopt a DFG-out activation loop conformation. Comparison with the structure of FGFR1 in complex with the candidate drug AZD4547, combined with kinetic characterization of the binding of ponatinib and AZD4547 to FGFR1 and FGFR4, sheds light on the observed differences in selectivity profiles and provides a rationale for developing FGFR4-selective inhibitors.


  • Organizational Affiliation

    Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FIBROBLAST GROWTH FACTOR RECEPTOR 4309Homo sapiensMutation(s): 1 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P22455 (Homo sapiens)
Explore P22455 
Go to UniProtKB:  P22455
PHAROS:  P22455
GTEx:  ENSG00000160867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22455
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0LI
Query on 0LI

Download Ideal Coordinates CCD File 
C [auth A]3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide
C29 H27 F3 N6 O
PHXJVRSECIGDHY-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
0LI Binding MOAD:  4UXQ Kd: 16 (nM) from 1 assay(s)
BindingDB:  4UXQ IC50: min: 7.1, max: 8 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.205 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.835α = 90
b = 58.371β = 96.48
c = 60.57γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-12-03
    Type: Initial release
  • Version 1.1: 2014-12-10
    Changes: Database references, Other
  • Version 1.2: 2014-12-17
    Changes: Database references