 |
PDBsum entry 4v05
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Structural insights into fgfr kinase isoform selectivity: diverse binding modes of azd4547 and ponatinib in complex with fgfr1 and fgfr4.
|
|
|
Authors
|
|
J.A.Tucker,
T.Klein,
J.Breed,
A.L.Breeze,
R.Overman,
C.Phillips,
R.A.Norman.
|
|
|
Ref.
|
|
Structure, 2014,
22,
1764-1774.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
