4u79
From Proteopedia
Crystal structure of human JNK3 in complex with a benzenesulfonamide inhibitor.
Structural highlights
DiseaseMK10_HUMAN Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:606369. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. FunctionMK10_HUMAN Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons.[1] Publication Abstract from PubMedThe kinase/endonuclease inositol requiring enzyme 1 (IRE1alpha), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1alpha endonuclease activity that bound to the kinase site on the enzyme. Structure-activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1alpha endonuclease as well as cellular IRE1alpha. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1alpha was obtained. Screening of native tumor cell lines (>300) against selective IRE1alpha inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1alpha activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis. Unfolded Protein Response in Cancer: IRE1alpha Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability.,Harrington PE, Biswas K, Malwitz D, Tasker AS, Mohr C, Andrews KL, Dellamaggiore K, Kendall R, Beckmann H, Jaeckel P, Materna-Reichelt S, Allen JR, Lipford JR ACS Med Chem Lett. 2014 Sep 24;6(1):68-72. doi: 10.1021/ml500315b. eCollection, 2015 Jan 8. PMID:25589933[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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