4QQT

Crystal Structure of FGF Receptor (FGFR) 4 Tyrosine Kinase Domain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.223 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

DFG-out Mode of Inhibition by an Irreversible Type-1 Inhibitor Capable of Overcoming Gate-Keeper Mutations in FGF Receptors.

Huang, Z.Tan, L.Wang, H.Liu, Y.Blais, S.Deng, J.Neubert, T.A.Gray, N.S.Li, X.Mohammadi, M.

(2015) ACS Chem Biol 10: 299-309

  • DOI: https://doi.org/10.1021/cb500674s
  • Primary Citation of Related Structures:  
    4QQ5, 4QQJ, 4QQT, 4QRC

  • PubMed Abstract: 

    Drug-resistance acquisition through kinase gate-keeper mutations is a major hurdle in the clinic. Here, we determined the first crystal structures of the human FGFR4 kinase domain (FGFR4K) alone and complexed with ponatinib, a promiscuous type-2 (DFG-out) kinase inhibitor, and an oncogenic FGFR4K harboring the V550L gate-keeper mutation bound to FIIN-2, a new type-1 irreversible inhibitor. Remarkably, like ponatinib, FIIN-2 also binds in the DFG-out mode despite lacking a functional group necessary to occupy the pocket vacated upon the DFG-out flip. Structural analysis reveals that the covalent bond between FIIN-2 and a cysteine, uniquely present in the glycine-rich loop of FGFR kinases, facilitates the DFG-out conformation, which together with the internal flexibility of FIIN-2 enables FIIN-2 to avoid the steric clash with the gate-keeper mutation that causes the ponatinib resistance. The structural data provide a blueprint for the development of next generation anticancer inhibitors through combining the salient inhibitory mechanisms of ponatinib and FIIN-2.


  • Organizational Affiliation

    School of Pharmacy, Wenzhou Medical University , Wenzhou, Zhejiang 325035, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fibroblast growth factor receptor 4323Homo sapiensMutation(s): 2 
Gene Names: FGFR4JTK2TKF
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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.223 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.384α = 90
b = 61.336β = 99.01
c = 61.084γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-29
    Type: Initial release
  • Version 1.1: 2015-01-28
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description