2zdu | pdb_00002zdu
Crystal Structure of human JNK3 complexed with an isoquinolone inhibitor
Structural highlights
Disease[MK10_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. Function[MK10_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] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedA novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modification at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed. Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1).,Asano Y, Kitamura S, Ohra T, Aso K, Igata H, Tamura T, Kawamoto T, Tanaka T, Sogabe S, Matsumoto S, Yamaguchi M, Kimura H, Itoh F Bioorg Med Chem. 2008 Apr 15;16(8):4715-32. Epub 2008 Feb 13. PMID:18313304[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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