5y86: Difference between revisions
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==Crystal structure of kinase== | |||
<StructureSection load='5y86' size='340' side='right'caption='[[5y86]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5y86]] 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=5Y86 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5Y86 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]] 1.9Å</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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HRM:7-METHOXY-1-METHYL-9H-BETA-CARBOLINE'>HRM</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=5y86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y86 OCA], [https://pdbe.org/5y86 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5y86 RCSB], [https://www.ebi.ac.uk/pdbsum/5y86 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5y86 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DYRK3_HUMAN DYRK3_HUMAN] Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. Negative regulator of EPO-dependent erythropoiesis, may place an upper limit on red cell production during stress erythropoiesis. Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells (PubMed:10779429). May act by regulating CREB/CRE signaling (By similarity). Stabilizes and prevents stress granule disassembly thereby regulating mTORC1 signaling during cellular stress. During stressful conditions, DYRK3 partitions to the stress granule from the cytosol, as well as mTORC1 components, which prevents mTORC1 signaling. When stress signals are gone, the kinase activity of DYRK3 is required for the dissolution of stress granule and mTORC1 relocation to the cytosol, and promotes the phosphorylation of the mTORC1 inhibitor, AKT1S1, allowing full reactivation of mTORC1 signaling (PubMed:23415227). Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1. This in turn inhibits TP53 activity and apoptosis (PubMed:20167603).[UniProtKB:Q922Y0]<ref>PMID:10779429</ref> <ref>PMID:20167603</ref> <ref>PMID:23415227</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Dual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia. | |||
Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation.,Kim K, Cha JS, Cho YS, Kim H, Chang N, Kim HJ, Cho HS J Mol Biol. 2018 Apr 7. pii: S0022-2836(18)30189-X. doi:, 10.1016/j.jmb.2018.04.001. PMID:29634919<ref>PMID:29634919</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5y86" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: Cho | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | |||
[[Category: Cha JS]] | |||
[[Category: Chang NP]] | |||
[[Category: Cho HS]] | |||
[[Category: Cho YS]] | |||
[[Category: Kim HY]] | |||
[[Category: Kim KL]] | |||
Latest revision as of 11:24, 22 November 2023
Crystal structure of kinaseCrystal structure of kinase
Structural highlights
FunctionDYRK3_HUMAN Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. Negative regulator of EPO-dependent erythropoiesis, may place an upper limit on red cell production during stress erythropoiesis. Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells (PubMed:10779429). May act by regulating CREB/CRE signaling (By similarity). Stabilizes and prevents stress granule disassembly thereby regulating mTORC1 signaling during cellular stress. During stressful conditions, DYRK3 partitions to the stress granule from the cytosol, as well as mTORC1 components, which prevents mTORC1 signaling. When stress signals are gone, the kinase activity of DYRK3 is required for the dissolution of stress granule and mTORC1 relocation to the cytosol, and promotes the phosphorylation of the mTORC1 inhibitor, AKT1S1, allowing full reactivation of mTORC1 signaling (PubMed:23415227). Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1. This in turn inhibits TP53 activity and apoptosis (PubMed:20167603).[UniProtKB:Q922Y0][1] [2] [3] Publication Abstract from PubMedDual-specificity tyrosine-regulated kinases (DYRKs) auto-phosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. The auto-phosphorylation occurs intramolecularly and is a one-off event. DYRK3 is selectively expressed at a high level in hematopoietic cells and attenuates erythroblast development, leading to anemia. In the present study, we determined the crystal structure of the mature form of human DYRK3 in complex with harmine, an ATP competitive inhibitor. The crystal structure revealed a phosphorylation site, residue S350, whose phosphorylation increases the stability of DYRK3 and enhances its kinase activity. In addition, our structural and biochemical assays suggest that the N-terminal auto-phosphorylation accessory domain stabilizes the DYRK3 protein, followed by auto-phosphorylation of the tyrosine of the activation loop, which is important for kinase activity. Finally, our docking analysis provides information for the design of novel and potent therapeutics to treat anemia. Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation.,Kim K, Cha JS, Cho YS, Kim H, Chang N, Kim HJ, Cho HS J Mol Biol. 2018 Apr 7. pii: S0022-2836(18)30189-X. doi:, 10.1016/j.jmb.2018.04.001. PMID:29634919[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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