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| <StructureSection load='7dhh' size='340' side='right'caption='[[7dhh]], [[Resolution|resolution]] 2.49Å' scene=''> | | <StructureSection load='7dhh' size='340' side='right'caption='[[7dhh]], [[Resolution|resolution]] 2.49Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7dhh]] 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=7DHH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DHH FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DHH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DHH 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]] 2.486Å</td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.486Å</td></tr> |
| <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H7L:[9-(azetidin-3-ylmethylsulfanyl)-2,7-dimethoxy-acridin-4-yl]methanol'>H7L</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H7L:[9-(azetidin-3-ylmethylsulfanyl)-2,7-dimethoxy-acridin-4-yl]methanol'>H7L</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=7dhh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dhh OCA], [https://pdbe.org/7dhh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dhh RCSB], [https://www.ebi.ac.uk/pdbsum/7dhh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dhh ProSAT]</span></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=7dhh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dhh OCA], [https://pdbe.org/7dhh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dhh RCSB], [https://www.ebi.ac.uk/pdbsum/7dhh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dhh ProSAT]</span></td></tr> |
| </table> | | </table> |
| == Function ==
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| [https://www.uniprot.org/uniprot/DYRK2_HUMAN DYRK2_HUMAN] Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser-641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).<ref>PMID:9748265</ref> <ref>PMID:11311121</ref> <ref>PMID:12588975</ref> <ref>PMID:14593110</ref> <ref>PMID:15910284</ref> <ref>PMID:16611631</ref> <ref>PMID:16511445</ref> <ref>PMID:17349958</ref> <ref>PMID:18599021</ref> <ref>PMID:18455992</ref> <ref>PMID:19287380</ref> <ref>PMID:22307329</ref> <ref>PMID:22878263</ref>
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| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| The dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 has emerged as a critical regulator of cellular processes. We took a chemical biology approach to gain further insights into its function. We developed C17, a potent small-molecule DYRK2 inhibitor, through multiple rounds of structure-based optimization guided by several co-crystallized structures. C17 displayed an effect on DYRK2 at a single-digit nanomolar IC50 and showed outstanding selectivity for the human kinome containing 467 other human kinases. Using C17 as a chemical probe, we further performed quantitative phosphoproteomic assays and identified several novel DYRK2 targets, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and stromal interaction molecule 1 (STIM1). DYRK2 phosphorylated 4E-BP1 at multiple sites, and the combined treatment of C17 with AKT and MEK inhibitors showed synergistic 4E-BP1 phosphorylation suppression. The phosphorylation of STIM1 by DYRK2 substantially increased the interaction of STIM1 with the ORAI1 channel, and C17 impeded the store-operated calcium entry process. These studies collectively further expand our understanding of DYRK2 and provide a valuable tool to pinpoint its biological function.
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| Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry.,Wei T, Wang J, Liang R, Chen W, Chen Y, Ma M, He A, Du Y, Zhou W, Zhang Z, Zeng X, Wang C, Lu J, Guo X, Chen XW, Wang Y, Tian R, Xiao J, Lei X Elife. 2022 Apr 19;11. pii: 77696. doi: 10.7554/eLife.77696. PMID:35439114<ref>PMID:35439114</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 7dhh" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Homo sapiens]]
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| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Wei T]] | | [[Category: Wei T]] |
| [[Category: Xiao J]] | | [[Category: Xiao J]] |