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PDBsum entry 4bkj
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References listed in PDB file
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Key reference
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Title
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Structural mechanisms determining inhibition of the collagen receptor ddr1 by selective and multi-Targeted type ii kinase inhibitors.
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Authors
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P.Canning,
L.Tan,
K.Chu,
S.W.Lee,
N.S.Gray,
A.N.Bullock.
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Ref.
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J Mol Biol, 2014,
426,
2457-2470.
[DOI no: ]
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PubMed id
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Abstract
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The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of
receptor tyrosine kinases that are activated by the binding of triple-helical
collagen. Excessive signaling by DDR1 and DDR2 has been linked to the
progression of various human diseases, including fibrosis, atherosclerosis and
cancer. We report the inhibition of these unusual receptor tyrosine kinases by
the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective
type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent
molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM. Co-crystal
structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the
kinase domain that is stabilized by an unusual salt bridge between the
activation loop and αD helix. Differences to Abelson kinase (ABL) are observed
in the DDR1 P-loop, where a β-hairpin replaces the cage-like structure of ABL.
P-loop residues in DDR1 that confer drug resistance in ABL are therefore
accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind
potently to both the DDR and ABL kinases, the hydrophobic interactions of the
ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis
for its DDR1 selectivity. Such inhibitors may have applications in clinical
indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.
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