2h96

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{{Seed}}
 
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[[Image:2h96.png|left|200px]]
 
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==Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide C-jun NH2-terminal Kinase Inhibitors==
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The line below this paragraph, containing "STRUCTURE_2h96", creates the "Structure Box" on the page.
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<StructureSection load='2h96' size='340' side='right'caption='[[2h96]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2h96]] is a 4 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=2H96 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2H96 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=893:5-CYANO-N-(2,5-DIMETHOXYBENZYL)-6-ETHOXYPYRIDINE-2-CARBOXAMIDE'>893</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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{{STRUCTURE_2h96| PDB=2h96 | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2h96 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h96 OCA], [https://pdbe.org/2h96 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2h96 RCSB], [https://www.ebi.ac.uk/pdbsum/2h96 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2h96 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/MK08_HUMAN MK08_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 MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH.<ref>PMID:16581800</ref> <ref>PMID:17296730</ref> <ref>PMID:18307971</ref> <ref>PMID:18570871</ref> <ref>PMID:20027304</ref> <ref>PMID:21364637</ref> <ref>PMID:21095239</ref> <ref>PMID:21856198</ref> JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms.<ref>PMID:16581800</ref> <ref>PMID:17296730</ref> <ref>PMID:18307971</ref> <ref>PMID:18570871</ref> <ref>PMID:20027304</ref> <ref>PMID:21364637</ref> <ref>PMID:21095239</ref> <ref>PMID:21856198</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/h9/2h96_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2h96 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.
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===Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide C-jun NH2-terminal Kinase Inhibitors===
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Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-Jun NH2-terminal kinase inhibitors.,Zhao H, Serby MD, Xin Z, Szczepankiewicz BG, Liu M, Kosogof C, Liu B, Nelson LT, Johnson EF, Wang S, Pederson T, Gum RJ, Clampit JE, Haasch DL, Abad-Zapatero C, Fry EH, Rondinone C, Trevillyan JM, Sham HL, Liu G J Med Chem. 2006 Jul 27;49(15):4455-8. PMID:16854050<ref>PMID:16854050</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2h96" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_16854050}}, adds the Publication Abstract to the page
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*[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 16854050 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_16854050}}
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__TOC__
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</StructureSection>
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==About this Structure==
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2H96 is a 4 chains structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H96 OCA].
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==Reference==
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<ref group="xtra">PMID:16854050</ref><ref group="xtra">PMID:16759099</ref><ref group="xtra">PMID:16527482</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Mitogen-activated protein kinase]]
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[[Category: Large Structures]]
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[[Category: Abad-Zapatero, C.]]
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[[Category: Abad-Zapatero C]]
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[[Category: C-jun n-terminal kinase]]
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[[Category: Jnk1]]
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[[Category: Protein kinase jnk1 inhibitor]]
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[[Category: Pyridine carboxamide inhibitor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 04:49:29 2009''
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Current revision

Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide C-jun NH2-terminal Kinase Inhibitors

PDB ID 2h96

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