6y23

DDR1 kinase autoinhibited by its juxtamembrane region

spinqualitylabelsall models 6y23, resolution 2.58Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6y23 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.58Å Ligands: SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DDR1_HUMAN Publication Abstract from PubMed Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase with important functions in organogenesis and tissue homeostasis. Aberrant DDR1 activity contributes to the progression of human diseases, including fibrosis and cancer. How DDR1 activity is regulated is poorly understood. We investigated the function of the long intracellular juxtamembrane (JM) region of human DDR1 and found that the kinase-proximal segment, JM4, is an important regulator of kinase activity. Crystal structure analysis revealed that JM4 forms a hairpin that penetrates the kinase active site, reinforcing autoinhibition by the activation loop. Using in vitro enzymology with soluble kinase constructs, we established that release from autoinhibition occurs in two distinct steps: rapid autophosphorylation of the JM4 tyrosines, Tyr569 and Tyr586, followed by slower autophosphorylation of activation loop tyrosines. Mutation of JM4 tyrosines abolished collagen-induced DDR1 activation in cells. The insights may be used to develop allosteric, DDR1-specific, kinase inhibitors. Two-step release of kinase autoinhibition in discoidin domain receptor 1.,Sammon D, Hohenester E, Leitinger B Proc Natl Acad Sci U S A. 2020 Sep 8;117(36):22051-22060. doi:, 10.1073/pnas.2007271117. Epub 2020 Aug 24. PMID:32839343 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Epithelial discoidin domain-containing receptor

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