4ckr | pdb_00004ckr

Crystal structure of the human DDR1 kinase domain in complex with DDR1-IN-1

spinqualitylabelsall models 4ckr, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ckr is a 1 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 4bki. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: DI1, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DDR1_HUMAN Publication Abstract from PubMed The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 A DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the 'DFG-out' conformation and inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with good selectivity as assessed against a panel of 451 kinases measured using the KinomeScan technology. We identified a mutation in the hinge region of DDR1, G707A, that confers >20-fold resistance to the ability of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to establish what pharmacology is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction. Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor.,Kim HG, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, Ezell SA, Wu H, Zhao Z, Wang J, Mandinova A, Griffin JD, Bullock AN, Liu Q, Lee SW, Gray NS ACS Chem Biol. 2013 Oct 18;8(10):2145-50. doi: 10.1021/cb400430t. Epub 2013 Aug, 13. PMID:23899692 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Epithelial discoidin domain-containing receptor

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