3HV3

Human p38 MAP Kinase in Complex with RL49

Summary for 3HV3

• Entry DOI: 10.2210/pdb3hv3/pdb
• Related: 3GCP 3GCQ 3GCS 3GCU 3GCV 3HV4 3HV5 3HV6 3HV7
• Descriptor: Mitogen-activated protein kinase 14, 1-{4-[(6-aminoquinolin-4-yl)amino]phenyl}-3-[3-tert-butyl-1-(3-methylphenyl)-1H-pyrazol-5-yl]urea, octyl beta-D-glucopyranoside, ... (5 entities in total)
• Functional Keywords: dfg-out, type ii, rl49, quinoline-pyrazolourea, hybrid, atp-binding, kinase, nucleotide-binding, nucleus, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 42125.05

Authors

Gruetter, C.,Simard, J.R.,Getlik, M.,Rauh, D. (deposition date: 2009-06-15, release date: 2009-11-17, Last modification date: 2023-09-06)

Primary citation

Kluter, S.,Grutter, C.,Naqvi, T.,Rabiller, M.,Simard, J.R.,Pawar, V.,Getlik, M.,Rauh, D.
Displacement assay for the detection of stabilizers of inactive kinase conformations.
J.Med.Chem., 53:357-367, 2010

PubMed Abstract: Targeting protein kinases with small molecules outside the highly conserved ATP pocket to stabilize inactive kinase conformations is becoming a more desirable approach in kinase inhibitor research, since these molecules have advanced pharmacological properties compared to compounds exclusively targeting the ATP pocket. Traditional screening approaches for kinase inhibitors are often based on enzyme activity, but they may miss inhibitors that stabilize inactive kinase conformations by enriching the active state of the kinase. Here we present the development of a kinase binding assay employing a pyrazolourea type III inhibitor and enzyme fragment complementation (EFC) technology that is suitable to screen stabilizers of enzymatically inactive kinases. To validate this assay system, we report the binding characteristics of a series of kinase inhibitors to inactive p38alpha and JNK2. Additionally, we present protein X-ray crystallography studies to examine the binding modes of potent quinoline-based DFG-out binders in p38alpha.

PubMed: 19928858
DOI: 10.1021/jm901297e

Experimental method

X-RAY DIFFRACTION (2 Å)