5x5o

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<StructureSection load='5x5o' size='340' side='right'caption='[[5x5o]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
<StructureSection load='5x5o' size='340' side='right'caption='[[5x5o]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5x5o]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X5O OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5X5O FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5x5o]] is a 1 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=5X5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5X5O FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7Z0:N-[2,4-bis(fluoranyl)-3-[2-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]phenyl]-3-bromanyl-benzenesulfonamide'>7Z0</scene></td></tr>
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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]] 1.868&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7Z0:N-[2,4-bis(fluoranyl)-3-[2-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]phenyl]-3-bromanyl-benzenesulfonamide'>7Z0</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5x5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x5o OCA], [http://pdbe.org/5x5o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x5o RCSB], [http://www.ebi.ac.uk/pdbsum/5x5o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x5o ProSAT]</span></td></tr>
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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=5x5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x5o OCA], [https://pdbe.org/5x5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5x5o RCSB], [https://www.ebi.ac.uk/pdbsum/5x5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5x5o ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/M3K20_HUMAN M3K20_HUMAN] Split-foot malformation-mesoaxial polydactyly syndrome;Congenital fiber-type disproportion myopathy. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/MLTK_HUMAN MLTK_HUMAN]] Stress-activated component of a protein kinase signal transduction cascade. Regulates the JNK and p38 pathways. Pro-apoptotic. Role in regulation of S and G2 cell cycle checkpoint by direct phosphorylation of CHEK2. Isoform 1, but not isoform 2, causes cell shrinkage and disruption of actin stress fibers. Isoform 1 may have role in neoplastic cell transformation and cancer development. Isoform 1, but not isoform 2, phosphorylates histone H3 at 'Ser-28'.<ref>PMID:10924358</ref> <ref>PMID:11042189</ref> <ref>PMID:11836244</ref> <ref>PMID:15172994</ref> <ref>PMID:15342622</ref> <ref>PMID:15684425</ref>
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[https://www.uniprot.org/uniprot/M3K20_HUMAN M3K20_HUMAN] Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation (PubMed:10924358, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15350844, PubMed:15737997, PubMed:18331592, PubMed:20559024, PubMed:32610081, PubMed:32289254, PubMed:35857590, PubMed:26999302). Acts by catalyzing phosphorylation of MAP kinase kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11042189, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15172994, PubMed:15737997, PubMed:32610081, PubMed:32289254, PubMed:35857590). Activates JNK through phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6 (PubMed:11836244, PubMed:12220515). Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress (PubMed:15350844, PubMed:21224381, PubMed:27859413). May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 (PubMed:15342622).<ref>PMID:10924358</ref> <ref>PMID:11042189</ref> <ref>PMID:11836244</ref> <ref>PMID:12220515</ref> <ref>PMID:14521931</ref> <ref>PMID:15172994</ref> <ref>PMID:15342622</ref> <ref>PMID:15350844</ref> <ref>PMID:15737997</ref> <ref>PMID:18331592</ref> <ref>PMID:20559024</ref> <ref>PMID:21224381</ref> <ref>PMID:26999302</ref> <ref>PMID:27859413</ref> <ref>PMID:32289254</ref> <ref>PMID:32610081</ref> <ref>PMID:35857590</ref> Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation (PubMed:32610081, PubMed:32289254, PubMed:35857590). Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR): directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes (PubMed:32610081, PubMed:32289254). Upon ribosome collisions, activates either the stress-activated protein kinase signal transduction cascade or the integrated stress response (ISR), leading to programmed cell death or cell survival, respectively (PubMed:32610081). Dangerous levels of ribosome collisions trigger the autophosphorylation and activation of MAP3K20, which dissociates from colliding ribosomes and phosphorylates MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 pathways that promote programmed cell death (PubMed:32610081, PubMed:32289254). Less dangerous levels of ribosome collisions trigger the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 independently of its protein-kinase activity, promoting EIF2AK4/GCN2-mediated phosphorylation of EIF2S1/eIF-2-alpha (PubMed:32610081). Also part of the stress-activated protein kinase signaling cascade triggering the NLRP1 inflammasome in response to UV-B irradiation: ribosome collisions activate MAP3K20, which directly phosphorylates NLRP1, leading to activation of the NLRP1 inflammasome and subsequent pyroptosis (PubMed:35857590). NLRP1 is also phosphorylated by MAP kinase p38 downstream of MAP3K20 (PubMed:35857590). Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) (PubMed:15684425).<ref>PMID:15684425</ref> <ref>PMID:32289254</ref> <ref>PMID:32610081</ref> <ref>PMID:35857590</ref> Isoform that lacks the C-terminal region that mediates ribosome-binding: does not act as a sensor of ribosome collisions in response to ribotoxic stress (PubMed:32610081, PubMed:32289254, PubMed:35857590). May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha (PubMed:27859413).<ref>PMID:27859413</ref> <ref>PMID:32289254</ref> <ref>PMID:32610081</ref> <ref>PMID:35857590</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A series of N-(3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides were designed as the first class of highly selective ZAK inhibitors. The representative compound 3h strongly inhibits the kinase activity of ZAK with an IC50 of 3.3 nM and dose-dependently suppresses the activation of ZAK downstream signals in vitro and in vivo, while it is significantly less potent for the majority of 403 nonmutated kinases evaluated. Compound 3h also exhibits orally therapeutic effects on cardiac hypertrophy in a spontaneous hypertensive rat model.
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Structure Based Design of N-(3-((1H-Pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile-alpha Motif Kinase (ZAK) Inhibitors.,Chang Y, Lu X, Shibu MA, Dai YB, Luo J, Zhang Y, Li Y, Zhao P, Zhang Z, Xu Y, Tu ZC, Zhang QW, Yun CH, Huang CY, Ding K J Med Chem. 2017 Jul 13;60(13):5927-5932. doi: 10.1021/acs.jmedchem.7b00572. Epub, 2017 Jun 16. PMID:28586211<ref>PMID:28586211</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 5x5o" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Mitogen-activated protein kinase kinase kinase]]
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[[Category: Dai YB]]
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[[Category: Dai, Y B]]
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[[Category: Yun CH]]
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[[Category: Yun, C H]]
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[[Category: Zhao P]]
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[[Category: Zhao, P]]
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[[Category: Inhibitor]]
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[[Category: Kinase]]
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[[Category: Transferase]]
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[[Category: Zak]]
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Current revision

Crystal structure of ZAK in complex with compound D2829

PDB ID 5x5o

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