4R6V

Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.179 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.

Tan, L.Wang, J.Tanizaki, J.Huang, Z.Aref, A.R.Rusan, M.Zhu, S.J.Zhang, Y.Ercan, D.Liao, R.G.Capelletti, M.Zhou, W.Hur, W.Kim, N.Sim, T.Gaudet, S.Barbie, D.A.Yeh, J.R.Yun, C.H.Hammerman, P.S.Mohammadi, M.Janne, P.A.Gray, N.S.

(2014) Proc Natl Acad Sci U S A 111: E4869-E4877

  • DOI: https://doi.org/10.1073/pnas.1403438111
  • Primary Citation of Related Structures:  
    4QQC, 4R5S, 4R6V

  • PubMed Abstract: 

    The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.


  • Organizational Affiliation

    Departments of Biological Chemistry and Molecular Pharmacology, Departments of Cancer Biology and.


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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FI3
Query on FI3

Download Ideal Coordinates CCD File 
B [auth A]N-[4-({[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl](6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino}methyl)phenyl]propanamide
C34 H38 Cl2 N8 O4
JQGSJUDIVJFQRL-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.179 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 139.381α = 90
b = 139.381β = 90
c = 50.09γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-29
    Type: Initial release
  • Version 1.1: 2014-11-26
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description