2WU6

Crystal Structure of the Human CLK3 in complex with DKI

2WU6 の概要

• エントリーDOI: 10.2210/pdb2wu6/pdb
• 関連するPDBエントリー: 2EU9 2EXE 2WU7
• 分子名称: DUAL SPECIFICITY PROTEIN KINASE CLK3, 5-AMINO-3-{[4-(AMINOSULFONYL)PHENYL]AMINO}-N-(2,6-DIFLUOROPHENYL)-1H-1,2,4-TRIAZOLE-1-CARBOTHIOAMIDE, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: transferase, kinase, tyrosine-protein kinase, serine/threonine-protein kinase, nucleotide-binding
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform 1: Nucleus. Isoform 2: Nucleus speckle: P49761
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46092.72

構造登録者

Muniz, J.R.C.,Fedorov, O.,King, O.,Filippakopoulos, P.,Bullock, A.N.,Philips, C.,Heightman, T.,Ugochukwu, E.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Knapp, S. (登録日: 2009-09-30, 公開日: 2009-10-20, 最終更新日: 2024-05-08)

主引用文献

Fedorov, O.,Huber, K.,Eisenreich, A.,Filippakopoulos, P.,King, O.,Bullock, A.N.,Szklarczyk, D.,Jensen, L.J.,Fabbro, D.,Trappe, J.,Rauch, U.,Bracher, F.,Knapp, S.
Specific Clk Inhibitors from a Novel Chemotype for Regulation of Alternative Splicing.
Chem.Biol, 18:67-, 2011

PubMed Abstract: There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix αC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19 effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue factor isoforms flTF (full-length TF) and asHTF (alternatively spliced human TF).

PubMed: 21276940
DOI: 10.1016/J.CHEMBIOL.2010.11.009

実験手法

X-RAY DIFFRACTION (1.92 Å)