6oyw

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'''Unreleased structure'''
 
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The entry 6oyw is ON HOLD until Paper Publication
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==ASK1 kinase domain in complex with Compound 11==
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<StructureSection load='6oyw' size='340' side='right'caption='[[6oyw]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6oyw]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OYW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OYW FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NKJ:(19S)-19-methyl-16,17,18,19-tetrahydro-8,4-(azeno)[1,2,4]triazolo[4,3-f][1,6,13]benzoxadiazacyclohexadecin-10(9H)-one'>NKJ</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6oyw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oyw OCA], [http://pdbe.org/6oyw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6oyw RCSB], [http://www.ebi.ac.uk/pdbsum/6oyw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6oyw ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/M3K5_HUMAN M3K5_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).<ref>PMID:8940179</ref> <ref>PMID:8974401</ref> <ref>PMID:9564042</ref> <ref>PMID:9774977</ref> <ref>PMID:10411906</ref> <ref>PMID:10849426</ref> <ref>PMID:10688666</ref> <ref>PMID:11689443</ref> <ref>PMID:11029458</ref> <ref>PMID:11154276</ref> <ref>PMID:14749717</ref> <ref>PMID:11920685</ref> <ref>PMID:12697749</ref> <ref>PMID:15023544</ref> <ref>PMID:14688258</ref> <ref>PMID:16129676</ref> <ref>PMID:17220297</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Structural analysis of a known apoptosis signal-regulating kinase 1 (ASK1) inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor 8 (cell IC50 = 1.2 muM). The profile of this compound was optimized for CNS penetration following two independent strategies: a rational design approach leading to 19 and a parallel synthesis approach leading to 26. Both analogs are potent ASK1 inhibitors in biochemical and cellular assays (19, cell IC50 = 95 nM; 26, cell IC50 = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK assay (19, ER = 5.2; 26, ER = 1.5). In vivo PK studies revealed that inhibitor 19 had moderate CNS penetration (Kpuu = 0.17) and analog 26 had high CNS penetration (Kpuu = 1.0).
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Authors: Marcotte, D.J.
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Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors.,Himmelbauer MK, Xin Z, Jones JH, Enyedy I, King K, Marcotte DJ, Murugan P, Santoro JC, Hesson T, Spilker K, Johnson JL, Luzzio MJ, Gilfillan R, de Turiso FG J Med Chem. 2019 Nov 26. doi: 10.1021/acs.jmedchem.9b01206. PMID:31710475<ref>PMID:31710475</ref>
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Description: ASK1 kinase domain in complex with Compound 11
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Marcotte, D.J]]
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<div class="pdbe-citations 6oyw" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Mitogen-activated protein kinase kinase kinase]]
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[[Category: Marcotte, D J]]
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[[Category: Ask1 map3k5]]
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[[Category: Transferase]]

Revision as of 06:51, 27 November 2019

ASK1 kinase domain in complex with Compound 11

PDB ID 6oyw

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