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Structural Mechanisms Determining Inhibition of the Collagen Receptor DDR1 by Selective and Multi-Targeted Type II Kinase Inhibitors

DOI: 10.1016/j.jmb.2014.04.014 DOI Help
PMID: 24768818 PMID Help

Authors: Peter Canning (Structural Genomics Consortium, University of Oxford) , Li Tan (Department of Cancer Biology, Dana Farber Cancer Institute, Boston, USA.) , Kiki Chu (Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, USA.) , Sam W. Lee (Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, USA.) , Nathanael S. Gray (Department of Cancer Biology, Dana Farber Cancer Institute, Boston, USA.) , Alex N. Bullock (Structural Genomics Consortium, University of Oxford, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology , VOL 426 (13) , PAGES 2457 - 2470

State: Published (Approved)
Published: June 2014
Diamond Proposal Number(s): 8421

Open Access Open Access

Abstract: 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 9 nM. 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.

Journal Keywords: Benzamides; Binding; Humans; Imidazoles; Models; Molecular; Piperazines; Protein; Secondary; Protein; Tertiary; Proto-Oncogene; Pyridazines; Pyrimidines; Receptor; Receptors; Collagen; Receptors; Mitogen; Sequence; Amino Acid

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)