6uip
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==DYRK1A Kinase Domain in Complex with a 6-azaindole Derivative, GNF2133.== | |
| + | <StructureSection load='6uip' size='340' side='right'caption='[[6uip]], [[Resolution|resolution]] 3.70Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6uip]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UIP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UIP FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q8J:4-ethyl-N-{4-[1-(oxan-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]pyridin-2-yl}piperazine-1-carboxamide'>Q8J</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='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=6uip FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uip OCA], [http://pdbe.org/6uip PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uip RCSB], [http://www.ebi.ac.uk/pdbsum/6uip PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uip ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == 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> | ||
| + | == 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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Autoimmune deficiency and destruction in either beta-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting beta-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human beta-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D). | ||
| - | + | Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.,Liu YA, Jin Q, Zou Y, Ding Q, Yan S, Wang Z, Hao X, Nguyen B, Zhang X, Pan J, Mo T, Jacobsen K, Lam T, Wu TY, Petrassi HM, Bursulaya B, DiDonato M, Gordon WP, Liu B, Baaten J, Hill R, Nguyen-Tran V, Qiu M, Zhang YQ, Kamireddy A, Espinola S, Deaton L, Ha S, Harb G, Jia Y, Li J, Shen W, Schumacher AM, Colman K, Glynne R, Pan S, McNamara P, Laffitte B, Meeusen S, Molteni V, Loren J J Med Chem. 2020 Feb 20. doi: 10.1021/acs.jmedchem.9b01624. PMID:32077280<ref>PMID:32077280</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6uip" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Dual-specificity kinase]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: DiDonato, M]] | ||
| + | [[Category: Spraggon, G]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 06:55, 4 March 2020
DYRK1A Kinase Domain in Complex with a 6-azaindole Derivative, GNF2133.
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