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==Structure of DYRK1A in complex with compound 4== | ==Structure of DYRK1A in complex with compound 4== | ||
<StructureSection load='7a4z' size='340' side='right'caption='[[7a4z]]' scene=''> | <StructureSection load='7a4z' size='340' side='right'caption='[[7a4z]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A4Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A4Z FirstGlance]. <br> | <table><tr><td colspan='2'>[[7a4z]] is a 1 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=7A4Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A4Z FirstGlance]. <br> | ||
</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=7a4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a4z OCA], [https://pdbe.org/7a4z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a4z RCSB], [https://www.ebi.ac.uk/pdbsum/7a4z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a4z ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6SD:3-(4-methoxyphenyl)-1~{H}-pyrazol-5-amine'>6SD</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>, <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]]</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=7a4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a4z OCA], [https://pdbe.org/7a4z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a4z RCSB], [https://www.ebi.ac.uk/pdbsum/7a4z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a4z ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
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<ref>PMID:34143631</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7a4z" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dual specificity tyrosine-phosphorylation-regulated kinase|Dual specificity tyrosine-phosphorylation-regulated kinase]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Dual-specificity kinase]] | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Dokurno P]] | [[Category: Dokurno, P]] | ||
[[Category: Hubbard | [[Category: Hubbard, R E]] | ||
[[Category: Surgenor | [[Category: Surgenor, A E]] | ||
[[Category: Fbld]] | |||
[[Category: Kinase]] | |||
[[Category: Phosphoprotein]] | |||
[[Category: Sbdd]] | |||
[[Category: Serine/threonine-protein kinase]] | |||
[[Category: Small molecule inhibitor]] | |||
[[Category: Transferase]] | |||
Revision as of 12:10, 21 July 2021
Structure of DYRK1A in complex with compound 4Structure of DYRK1A in complex with compound 4
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 PubMedThe 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. See AlsoReferences
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