Summary
PDB 3V6S deposited: 2011-12-20 modified: 2012-07-25
Title Discovery of potent and selective covalent inhibitors of JNK
Authors Alessi, D.R., Ficarro, S.B., Gray, N.S., Inesta-Vaquera, F., Kim, N., Laughlin, J.D., LoGrasso, P.V., Machleidt, T., Marto, J.A., Niepel, M., Nomanbhoy, T.K., Park, H., Patricelli, M., Sim, T., Sorger, P.K., Xie, T., Zhang, J., Zhang, T.
Method X-RAY DIFFRACTION
Structure factors resolution 2.97 rfactor 0.216 rfree 0.263
DPI 1.24 theoretical min: 0.57
Related PDB Entries 3V6R
Citations

The mitogen-activated kinases JNK1/2/3 are key enzymes in signaling modules that transduce and integrate extracellular stimuli into coordinated cellular response. Here, we report the discovery of irreversible inhibitors of JNK1/2/3. We describe two JNK3 cocrystal structures at 2.60 and 2.97 Å resolution that show the compounds form covalent bonds with a conserved cysteine residue. JNK-IN-8 is a selective JNK inhibitor that inhibits phosphorylation of c-Jun, a direct substrate of JNK, in cells exposed to submicromolar drug in a manner that depends on covalent modification of the conserved cysteine residue. Extensive biochemical, cellular, and pathway-based profiling establish the selectivity of JNK-IN-8 for JNK and suggests that the compound will be broadly useful as a pharmacological probe of JNK-dependent signal transduction. Potential lead compounds have also been identified for kinases, including IRAK1, PIK3C3, PIP4K2C, and PIP5K3.

Chem.Biol. 2012 Jan; 19(1):140-154 doi:10.1016/j.chembiol.2011.11.010

Cross References
Database source Identifier Description
PubMed 22284361 CBOLE2
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3V6S/1 3V6S 1 monomer 0 1 1 2640
3V6S/2 3V6S 2 monomer 0 1 1 2602