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| | ==Crystal structure of DYRK1AA in complex with 10-Bromo-substituted 11H-indolo[3,2-c]quinolone-6-carboxylic acid inhibitor 5t== | | ==Crystal structure of DYRK1AA in complex with 10-Bromo-substituted 11H-indolo[3,2-c]quinolone-6-carboxylic acid inhibitor 5t== |
| - | <StructureSection load='4yll' size='340' side='right' caption='[[4yll]], [[Resolution|resolution]] 1.40Å' scene=''> | + | <StructureSection load='4yll' size='340' side='right'caption='[[4yll]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4yll]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YLL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YLL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4yll]] 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=4YLL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YLL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4E3:10-BROMO-2-IODO-11H-INDOLO[3,2-C]QUINOLINE-6-CARBOXYLIC+ACID'>4E3</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4E3:10-BROMO-2-IODO-11H-INDOLO[3,2-C]QUINOLINE-6-CARBOXYLIC+ACID'>4E3</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4yll FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yll OCA], [https://pdbe.org/4yll PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yll RCSB], [https://www.ebi.ac.uk/pdbsum/4yll PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yll ProSAT]</span></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ylj|4ylj]], [[4ylk|4ylk]]</td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DYRK1A, DYRK, MNB, MNBH ([http://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'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4yll FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yll OCA], [http://pdbe.org/4yll PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yll RCSB], [http://www.ebi.ac.uk/pdbsum/4yll PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yll ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/DYR1A_HUMAN DYR1A_HUMAN]] Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:[http://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 == |
| - | [[http://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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dual-specificity kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Bountra, C]] | + | [[Category: Bountra C]] |
| - | [[Category: Chaikuad, A]] | + | [[Category: Chaikuad A]] |
| - | [[Category: Delft, F von]]
| + | [[Category: Edwards AM]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Falke H]] |
| - | [[Category: Falke, H]] | + | [[Category: Knapp S]] |
| - | [[Category: Knapp, S]] | + | [[Category: Krojer T]] |
| - | [[Category: Krojer, T]] | + | [[Category: Kunick C]] |
| - | [[Category: Kunick, C]] | + | [[Category: Von Delft F]] |
| - | [[Category: Structural genomic]] | + | |
| - | [[Category: Halogen]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
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 protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site.
10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A.,Falke H, Chaikuad A, Becker A, Loaec N, Lozach O, Abu Jhaisha S, Becker W, Jones PG, Preu L, Baumann K, Knapp S, Meijer L, Kunick C J Med Chem. 2015 Mar 23. PMID:25730262[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
- ↑ Falke H, Chaikuad A, Becker A, Loaec N, Lozach O, Abu Jhaisha S, Becker W, Jones PG, Preu L, Baumann K, Knapp S, Meijer L, Kunick C. 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A. J Med Chem. 2015 Mar 23. PMID:25730262 doi:http://dx.doi.org/10.1021/jm501994d
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