6t6a
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of DYRK1A complexed with KuFal319 (compound 11)== | |
| + | <StructureSection load='6t6a' size='340' side='right'caption='[[6t6a]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6t6a]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T6A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6T6A FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MLW:4-chloranyl-5~{H}-cyclohepta[b]indol-10-one'>MLW</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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='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=6t6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t6a OCA], [http://pdbe.org/6t6a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t6a RCSB], [http://www.ebi.ac.uk/pdbsum/6t6a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t6a 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 == | ||
| + | Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer's disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity. | ||
| - | + | [b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors.,Lechner C, Flasshoff M, Falke H, Preu L, Loaec N, Meijer L, Knapp S, Chaikuad A, Kunick C Molecules. 2019 Nov 13;24(22). pii: molecules24224090. doi:, 10.3390/molecules24224090. PMID:31766108<ref>PMID:31766108</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6t6a" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Dual-specificity kinase]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Arrowsmith, C H]] | ||
| + | [[Category: Bountra, C]] | ||
[[Category: Chaikuad, A]] | [[Category: Chaikuad, A]] | ||
| + | [[Category: Edwards, A M]] | ||
[[Category: Knapp, S]] | [[Category: Knapp, S]] | ||
| - | [[Category: Edwards, A.M]] | ||
| - | [[Category: Arrowsmith, C.H]] | ||
| - | [[Category: Structural Genomics Consortium (Sgc)]] | ||
[[Category: Kunick, C]] | [[Category: Kunick, C]] | ||
| - | [[Category: | + | [[Category: Structural genomic]] |
| + | [[Category: Dyrk1a]] | ||
| + | [[Category: Kinase inhibitor]] | ||
| + | [[Category: Sgc]] | ||
| + | [[Category: Splicing kinase]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 08:18, 4 December 2019
Crystal structure of DYRK1A complexed with KuFal319 (compound 11)
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