3npc
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of JNK2 complexed with BIRB796== | |
| + | <StructureSection load='3npc' size='340' side='right'caption='[[3npc]], [[Resolution|resolution]] 2.35Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[3npc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NPC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NPC FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B96:1-(5-TERT-BUTYL-2-P-TOLYL-2H-PYRAZOL-3-YL)-3-[4-(2-MORPHOLIN-4-YL-ETHOXY)-NAPHTHALEN-1-YL]-UREA'>B96</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3npc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3npc OCA], [https://pdbe.org/3npc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3npc RCSB], [https://www.ebi.ac.uk/pdbsum/3npc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3npc ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/MK09_HUMAN MK09_HUMAN] Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation 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 MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase 1-specific transcription initiation factor RRN3. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. Participates also in neurite growth in spiral ganglion neurons.<ref>PMID:10376527</ref> <ref>PMID:15805466</ref> <ref>PMID:17525747</ref> <ref>PMID:19675674</ref> <ref>PMID:20595622</ref> <ref>PMID:21364637</ref> MAPK9 isoforms display different binding patterns: alpha-1 and alpha-2 preferentially bind to JUN, whereas beta-1 and beta-2 bind to ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. JUNB is not a substrate for JNK2 alpha-2, and JUND binds only weakly to it.<ref>PMID:10376527</ref> <ref>PMID:15805466</ref> <ref>PMID:17525747</ref> <ref>PMID:19675674</ref> <ref>PMID:20595622</ref> <ref>PMID:21364637</ref> | ||
| + | == Evolutionary Conservation == | ||
| + | [[Image:Consurf_key_small.gif|200px|right]] | ||
| + | Check<jmol> | ||
| + | <jmolCheckbox> | ||
| + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/np/3npc_consurf.spt"</scriptWhenChecked> | ||
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
| + | <text>to colour the structure by Evolutionary Conservation</text> | ||
| + | </jmolCheckbox> | ||
| + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3npc ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | JNK2 and p38alpha are closely related mitogen-activated protein kinases that regulate various cellular activities and are considered drug targets for inflammatory diseases. We have determined the X-ray crystal structure of the clinical phase II p38alpha inhibitor BIRB796 bound to its off-target JNK2. This shows for the first time a JNK subfamily member in the DFG-out conformation. The fully resolved activation loop reveals that BIRB796 inhibits JNK2 activation by stabilizing the loop in a position that does not allow its phosphorylation by upstream kinases. The structure suggests that substituents at the BIRB796 morpholino group and modifications of the t-butyl moiety should further increase the p38alpha to JNK2 potency ratio. For the design of selective DFG-out binding JNK2 inhibitors, the binding pocket of the BIRB796 tolyl group may have the best potential. | ||
| - | + | X-ray crystal structure of JNK2 complexed with the p38alpha inhibitor BIRB796: insights into the rational design of DFG-out binding MAP kinase inhibitors.,Kuglstatter A, Ghate M, Tsing S, Villasenor AG, Shaw D, Barnett JW, Browner MF Bioorg Med Chem Lett. 2010 Sep 1;20(17):5217-20. Epub 2010 Jul 23. PMID:20655210<ref>PMID:20655210</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| + | </div> | ||
| + | <div class="pdbe-citations 3npc" style="background-color:#fffaf0;"></div> | ||
| - | + | ==See Also== | |
| + | *[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Ghate M]] | ||
| + | [[Category: Kuglstatter A]] | ||
Current revision
Crystal structure of JNK2 complexed with BIRB796
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