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| | <StructureSection load='7a52' size='340' side='right'caption='[[7a52]], [[Resolution|resolution]] 2.10Å' scene=''> | | <StructureSection load='7a52' size='340' side='right'caption='[[7a52]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7a52]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A52 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A52 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7a52]] 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=7A52 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A52 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=QYB:3-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one'>QYB</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]] 2.1Å</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>, <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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=QYB:3-phenyl-1H,4H,5H-pyrazolo[3,4-d]pyrimidin-4-one'>QYB</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7a4o|7a4o]], [[7a4r|7a4r]], [[7a4s|7a4s]], [[7a4w|7a4w]], [[7a4z|7a4z]], [[7a51|7a51]]</div></td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DYRK1A, DYRK, MNB, MNBH ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </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=7a52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a52 OCA], [https://pdbe.org/7a52 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a52 RCSB], [https://www.ebi.ac.uk/pdbsum/7a52 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a52 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=7a52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a52 OCA], [https://pdbe.org/7a52 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a52 RCSB], [https://www.ebi.ac.uk/pdbsum/7a52 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a52 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == 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>
| + | [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 == | | == 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>
| + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 7a52" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 7a52" style="background-color:#fffaf0;"></div> |
| - | | |
| - | ==See Also== | |
| - | *[[Dual specificity tyrosine-phosphorylation-regulated kinase|Dual specificity tyrosine-phosphorylation-regulated kinase]] | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dual-specificity kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Dokurno, P]] | + | [[Category: Dokurno P]] |
| - | [[Category: Hubbard, R E]] | + | [[Category: Hubbard RE]] |
| - | [[Category: Surgenor, A E]] | + | [[Category: Surgenor AE]] |
| - | [[Category: Fbld]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Sbdd]]
| + | |
| - | [[Category: Serine/threonine-protein kinase]]
| + | |
| - | [[Category: Small molecule inhibitor]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
7a52 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.1Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
DYR1A_HUMAN Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM: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.[1]
Function
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.[2]
Publication Abstract from PubMed
The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.
Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B.,Lee Walmsley D, Murray JB, Dokurno P, Massey AJ, Benwell K, Fiumana A, Foloppe N, Ray S, Smith J, Surgenor AE, Edmonds T, Demarles D, Burbridge M, Cruzalegui F, Kotschy A, Hubbard RE J Med Chem. 2021 Jun 18. doi: 10.1021/acs.jmedchem.1c00024. PMID:34143631[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ van Bon BW, Hoischen A, Hehir-Kwa J, de Brouwer AP, Ruivenkamp C, Gijsbers AC, Marcelis CL, de Leeuw N, Veltman JA, Brunner HG, de Vries BB. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin Genet. 2011 Mar;79(3):296-9. doi: 10.1111/j.1399-0004.2010.01544.x. PMID:21294719 doi:10.1111/j.1399-0004.2010.01544.x
- ↑ Shindoh N, Kudoh J, Maeda H, Yamaki A, Minoshima S, Shimizu Y, Shimizu N. Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21. Biochem Biophys Res Commun. 1996 Aug 5;225(1):92-9. PMID:8769099 doi:S0006-291X(96)91135-3
- ↑ Lee Walmsley D, Murray JB, Dokurno P, Massey AJ, Benwell K, Fiumana A, Foloppe N, Ray S, Smith J, Surgenor AE, Edmonds T, Demarles D, Burbridge M, Cruzalegui F, Kotschy A, Hubbard RE. Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B. J Med Chem. 2021 Jun 18. doi: 10.1021/acs.jmedchem.1c00024. PMID:34143631 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c00024
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