2VAG: Crystal Structure Of Di-Phosphorylated Human Clk1 In Complex With A Novel Substituted Indole Inhibitor

Citation:
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 alphaC 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).
PDB ID: 2VAGDownload
MMDB ID: 59824
PDB Deposition Date: 2007/8/31
Updated in MMDB: 2011/12
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Similar Structures:
Biological Unit for 2VAG: monomeric; determined by author and by software (PISA)
Molecular Components in 2VAG
Label Count Molecule
Protein (1 molecule)
1
Dual Specificity Protein Kinase Clk1(Gene symbol: CLK1)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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