8yev
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Dual-specificity tyrosine phosphorylation-regulated kinase 1A in complex with coumestrol== | |
| + | <StructureSection load='8yev' size='340' side='right'caption='[[8yev]], [[Resolution|resolution]] 2.25Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8yev]] is a 2 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=8YEV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8YEV 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]] 2.2515233Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CUE:COUMESTROL'>CUE</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=8yev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8yev OCA], [https://pdbe.org/8yev PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8yev RCSB], [https://www.ebi.ac.uk/pdbsum/8yev PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8yev ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN] Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:[https://omim.org/entry/614104 614104]. A disease characterized by primary microcephaly, severe mental retardation without speech, anxious autistic behavior, and dysmorphic features, including bitemporal narrowing, deep-set eyes, large simple ears, and a pointed nasal tip. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.<ref>PMID:21294719</ref> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN] May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Phosphorylates serine, threonine and tyrosine residues in its sequence and in exogenous substrates.<ref>PMID:8769099</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Alzheimer's disease (AD) is an irreversible neurodegenerative disease, with tau pathology caused by abnormally activated dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) being one of the culprits. Coumestrol, a phytoestrogen and natural antioxidant found in various plants, has been reported to alleviate AD, but the underlying mechanism remains unclear. We confirmed coumestrol as a novel DYRK1A inhibitor through enzyme-based assays, X-ray crystallography, and cell line experiments. Coumestrol exhibited minimal cytotoxicity at concentrations up to 100 muM in cell types such as N2A and SH-SY5Y and reduced DYRK1A-induced phosphorylated tau protein levels by >50 % at 60 muM. In the tau protein phosphorylation and microtubule assembly assay, coumestrol at 30 muM reduced phosphorylated tau by >50 % and restored the microtubule assembly process. Coumestrol also significantly reduced amyloid-beta (Abeta)-induced oxidative stress in microglia at 1 muM. In zebrafish larvae co-overexpressing DYRK1A and tau, coumestrol mitigated neuronal damage and protected motor function at 48 h-postfertilization. Our results suggest that coumestrol has potential therapeutic effects in AD by inhibiting DYRK1A, lowering p-Tau levels, restoring microtubule assembly, and protecting microglia cells from Abeta-induced cell death, providing new insights into the development of coumestrol as a potential AD treatment. | ||
| - | + | Identification, biological evaluation, and crystallographic analysis of coumestrol as a novel dual-specificity tyrosine-phosphorylation-regulated kinase 1A inhibitor.,Peng CH, Hwang TL, Hung SC, Tu HJ, Tseng YT, Lin TE, Lee CC, Tseng YC, Ko CY, Yen SC, Hsu KC, Pan SL, HuangFu WC Int J Biol Macromol. 2024 Dec;282(Pt 4):136860. doi: , 10.1016/j.ijbiomac.2024.136860. Epub 2024 Oct 29. PMID:39481728<ref>PMID:39481728</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Hsu | + | <div class="pdbe-citations 8yev" style="background-color:#fffaf0;"></div> |
| - | [[Category: Lee | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Hsu KC]] | ||
| + | [[Category: Lee CC]] | ||
Current revision
Dual-specificity tyrosine phosphorylation-regulated kinase 1A in complex with coumestrol
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