4CKR

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

「4BKI」から置き換えられました

4CKR の概要

• エントリーDOI: 10.2210/pdb4ckr/pdb
• 分子名称: EPITHELIAL DISCOIDIN DOMAIN-CONTAINING RECEPTOR 1, 4-[(4-ethylpiperazin-1-yl)methyl]-n-{4-methyl-3-[(2-oxo-2,3-dihydro-1h-indol-5-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: transferase, collagen, discoidin domain
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cell membrane; Single-pass type I membrane protein. Isoform 3: Secreted . Isoform 4: Cell membrane; Single-pass type I membrane protein: Q08345
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36617.02

構造登録者

Canning, P.,Elkins, J.M.,Goubin, S.,Mahajan, P.,Krojer, T.,Newman, J.A.,Dixon-Clarke, S.,Chaikuad, A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A. (登録日: 2014-01-07, 公開日: 2014-01-15, 最終更新日: 2023-12-20)

主引用文献

Kim, H.,Tan, L.,Weisberg, E.L.,Liu, F.,Canning, P.,Choi, H.G.,Ezell, S.A.,Wu, H.,Zhao, Z.,Wang, J.,Mandinova, A.,Griffin, J.D.,Bullock, A.N.,Liu, Q.,Lee, S.W.,Gray, N.S.
Discovery of a Potent and Selective Ddr1 Receptor Tyrosine Kinase Inhibitor.
Acs Chem.Biol., 8:2145-, 2013

PubMed Abstract: 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 Å 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.

PubMed: 23899692
DOI: 10.1021/CB400430T

実験手法

X-RAY DIFFRACTION (2.2 Å)