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| | <StructureSection load='7o7i' size='340' side='right'caption='[[7o7i]], [[Resolution|resolution]] 2.50Å' scene=''> | | <StructureSection load='7o7i' size='340' side='right'caption='[[7o7i]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7o7i]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7O7I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O7I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7o7i]] 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=7O7I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O7I FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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]] 2.5Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=7o7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o7i OCA], [https://pdbe.org/7o7i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o7i RCSB], [https://www.ebi.ac.uk/pdbsum/7o7i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o7i 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=7o7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o7i OCA], [https://pdbe.org/7o7i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o7i RCSB], [https://www.ebi.ac.uk/pdbsum/7o7i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o7i ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/HIPK3_HUMAN HIPK3_HUMAN]] Serine/threonine-protein kinase involved in transcription regulation, apoptosis and steroidogenic gene expression. Phosphorylates JUN and RUNX2. Seems to negatively regulate apoptosis by promoting FADD phosphorylation. Enhances androgen receptor-mediated transcription. May act as a transcriptional corepressor for NK homeodomain transcription factors. The phosphorylation of NR5A1 activates SF1 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. In osteoblasts, supports transcription activation: phosphorylates RUNX2 that synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE).<ref>PMID:14766760</ref> <ref>PMID:17210646</ref>
| + | [https://www.uniprot.org/uniprot/HIPK3_HUMAN HIPK3_HUMAN] Serine/threonine-protein kinase involved in transcription regulation, apoptosis and steroidogenic gene expression. Phosphorylates JUN and RUNX2. Seems to negatively regulate apoptosis by promoting FADD phosphorylation. Enhances androgen receptor-mediated transcription. May act as a transcriptional corepressor for NK homeodomain transcription factors. The phosphorylation of NR5A1 activates SF1 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. In osteoblasts, supports transcription activation: phosphorylates RUNX2 that synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE).<ref>PMID:14766760</ref> <ref>PMID:17210646</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]]
| + | [[Category: Anand K]] |
| - | [[Category: Anand, K]] | + | [[Category: Geyer M]] |
| - | [[Category: Geyer, M]] | + | [[Category: Kaltheuner IH]] |
| - | [[Category: Kaltheuner, I H]] | + | |
| - | [[Category: Cmgc kinase]]
| + | |
| - | [[Category: Homeodomain-interacting protein kinase]]
| + | |
| - | [[Category: Serine/threonine kinase]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
HIPK3_HUMAN Serine/threonine-protein kinase involved in transcription regulation, apoptosis and steroidogenic gene expression. Phosphorylates JUN and RUNX2. Seems to negatively regulate apoptosis by promoting FADD phosphorylation. Enhances androgen receptor-mediated transcription. May act as a transcriptional corepressor for NK homeodomain transcription factors. The phosphorylation of NR5A1 activates SF1 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. In osteoblasts, supports transcription activation: phosphorylates RUNX2 that synergizes with SPEN/MINT to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE).[1] [2]
Publication Abstract from PubMed
Homeodomain-interacting protein kinases (HIPKs) belong to the CMGC kinase family and are closely related to dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). HIPKs are regulators of various signaling pathways and involved in the pathology of cancer, chronic fibrosis, diabetes, and multiple neurodegenerative diseases. Here, we report the crystal structure of HIPK3 in its apo form at 2.5 A resolution. Recombinant HIPKs and DYRK1A are auto-activated and phosphorylate the negative elongation factor SPT5, the transcription factor c-Myc, and the C-terminal domain of RNA polymerase II, suggesting a direct function in transcriptional regulation. Based on a database search, we identified abemaciclib, an FDA-approved Cdk4/Cdk6 inhibitor used for the treatment of metastatic breast cancer, as potent inhibitor of HIPK2, HIPK3, and DYRK1A. We determined the crystal structures of HIPK3 and DYRK1A bound to abemaciclib, showing a similar binding mode to the hinge region of the kinase as observed for Cdk6. Remarkably, DYRK1A is inhibited by abemaciclib to the same extent as Cdk4/Cdk6 in vitro, raising the question of whether targeting of DYRK1A contributes to the transcriptional inhibition and therapeutic activity of abemaciclib.
Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation.,Kaltheuner IH, Anand K, Moecking J, Duster R, Wang J, Gray NS, Geyer M Nat Commun. 2021 Nov 16;12(1):6607. doi: 10.1038/s41467-021-26935-z. PMID:34785661[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Curtin JF, Cotter TG. JNK regulates HIPK3 expression and promotes resistance to Fas-mediated apoptosis in DU 145 prostate carcinoma cells. J Biol Chem. 2004 Apr 23;279(17):17090-100. doi: 10.1074/jbc.M307629200. Epub, 2004 Feb 6. PMID:14766760 doi:http://dx.doi.org/10.1074/jbc.M307629200
- ↑ Lan HC, Li HJ, Lin G, Lai PY, Chung BC. Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through homeodomain-interacting protein kinase 3-mediated Jun N-terminal kinase and c-Jun phosphorylation. Mol Cell Biol. 2007 Mar;27(6):2027-36. Epub 2007 Jan 8. PMID:17210646 doi:10.1128/MCB.02253-06
- ↑ Kaltheuner IH, Anand K, Moecking J, Duster R, Wang J, Gray NS, Geyer M. Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation. Nat Commun. 2021 Nov 16;12(1):6607. doi: 10.1038/s41467-021-26935-z. PMID:34785661 doi:http://dx.doi.org/10.1038/s41467-021-26935-z
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