3V6R

Discovery of potent and selective covalent inhibitors of JNK

Summary for 3V6R

• Entry DOI: 10.2210/pdb3v6r/pdb
• Related: 3V6S
• Descriptor: Mitogen-activated protein kinase 10, 4-{[4-(dimethylamino)butanoyl]amino}-N-(3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide (3 entities in total)
• Functional Keywords: kinase fold, apoptosis, map kinase, cys modification, phosphorylation, jnk, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P53779
• Total number of polymer chains: 2
• Total formula weight: 85110.50

Authors

Park, H.,LoGrasso, P.V.,Laughlin, J.D. (deposition date: 2011-12-20, release date: 2012-02-01, Last modification date: 2012-07-25)

Primary citation

Zhang, T.,Inesta-Vaquera, F.,Niepel, M.,Zhang, J.,Ficarro, S.B.,Machleidt, T.,Xie, T.,Marto, J.A.,Kim, N.,Sim, T.,Laughlin, J.D.,Park, H.,LoGrasso, P.V.,Patricelli, M.,Nomanbhoy, T.K.,Sorger, P.K.,Alessi, D.R.,Gray, N.S.
Discovery of potent and selective covalent inhibitors of JNK.
Chem.Biol., 19:140-154, 2012

PubMed Abstract: 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.

PubMed: 22284361
DOI: 10.1016/j.chembiol.2011.11.010

Experimental method

X-RAY DIFFRACTION (2.6 Å)