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6uwy
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==DYRK1A bound to a harmine derivative== | |
| + | <StructureSection load='6uwy' size='340' side='right'caption='[[6uwy]], [[Resolution|resolution]] 2.95Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6uwy]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UWY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UWY FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=QKG:4-(7-methoxy-1-methyl-9H-beta-carbolin-9-yl)butanamide'>QKG</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=6uwy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwy OCA], [http://pdbe.org/6uwy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uwy RCSB], [http://www.ebi.ac.uk/pdbsum/6uwy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwy 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 == | ||
| + | Recently, our group identified that harmine is able to induce beta-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from lack of selectivity, both against other kinases and CNS off-targets, therefore, we sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets, while retaining human beta-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human beta-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for beta-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much-improved in vivo lead candidate as compared to harmine, for the treatment of diabetes. | ||
| - | + | Synthesis and Biological Validation of a Harmine-based, Central Nervous System (CNS)-Avoidant, Selective, Human beta-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor.,Kumar K, Wang P, Wilson J, Zlatanic V, Berrouet C, Khamrui S, Secor C, Swartz E, Lazarus MB, Sanchez R, Stewart AF, Garcia-Ocana A, DeVita RJ J Med Chem. 2020 Jan 31. doi: 10.1021/acs.jmedchem.9b01379. PMID:32003560<ref>PMID:32003560</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6uwy" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Dual-specificity kinase]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Khamrui, S]] | ||
| + | [[Category: Lazarus, M B]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Transferase]] | ||
| + | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 04:29, 13 February 2020
DYRK1A bound to a harmine derivative
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