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PDBsum entry 4uxq
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PDB id:
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Transferase
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Title:
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Fgfr4 in complex with ponatinib
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Structure:
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Fibroblast growth factor receptor 4. Chain: a. Fragment: kinase domain, residues 447-753. Synonym: fgfr-4, fgfr4, cd334. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.85Å
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R-factor:
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0.205
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R-free:
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0.268
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Authors:
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J.Tucker,T.Klein,J.Breed,A.Breeze,R.Overman,C.Phillips,R.A.Norman
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Key ref:
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J.A.Tucker
et al.
(2014).
Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4.
Structure,
22,
1764-1774.
PubMed id:
DOI:
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Date:
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27-Aug-14
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Release date:
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03-Dec-14
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PROCHECK
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Headers
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References
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P22455
(FGFR4_HUMAN) -
Fibroblast growth factor receptor 4 from Homo sapiens
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Seq:
Struc:
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802 a.a.
286 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Structure
22:1764-1774
(2014)
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PubMed id:
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Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4.
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J.A.Tucker,
T.Klein,
J.Breed,
A.L.Breeze,
R.Overman,
C.Phillips,
R.A.Norman.
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ABSTRACT
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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.
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