View source for 5lxc


==Crystal structure of DYRK2 in complex with EHT 5372 (Compound 1)==
<StructureSection load='5lxc' size='340' side='right' caption='[[5lxc]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5lxc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LXC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LXC FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7AA:METHYL+9-[(2,4-DICHLOROPHENYL)AMINO]-[1,3]THIAZOLO[5,4-F]QUINAZOLINE-2-CARBOXIMIDATE'>7AA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=5lxc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lxc OCA], [http://pdbe.org/5lxc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lxc RCSB], [http://www.ebi.ac.uk/pdbsum/5lxc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lxc ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/DYRK2_HUMAN DYRK2_HUMAN]] Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser-641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).<ref>PMID:9748265</ref> <ref>PMID:11311121</ref> <ref>PMID:12588975</ref> <ref>PMID:14593110</ref> <ref>PMID:15910284</ref> <ref>PMID:16611631</ref> <ref>PMID:16511445</ref> <ref>PMID:17349958</ref> <ref>PMID:18599021</ref> <ref>PMID:18455992</ref> <ref>PMID:19287380</ref> <ref>PMID:22307329</ref> <ref>PMID:22878263</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Methyl 9-anilinothiazolo[5,4-f]quinazoline-2-carbimidates 1 (EHT 5372) and 2 (EHT 1610) are strong inhibitors of DYRK's family kinases. The crystal structures of the complex revealed a noncanonical binding mode of compounds 1 and 2 in DYRK2, explaining the remarkable selectivity and potency of these inhibitors. The structural data and comparison presented here provide therefore a template for further improvement of this inhibitor class and for the development of novel inhibitors selectively targeting DYRK kinases.

An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases.,Chaikuad A, Diharce J, Schroder M, Foucourt A, Leblond B, Casagrande AS, Desire L, Bonnet P, Knapp S, Besson T J Med Chem. 2016 Nov 23;59(22):10315-10321. Epub 2016 Nov 2. PMID:27766861<ref>PMID:27766861</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5lxc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Dual-specificity kinase]]
[[Category: Arrowsmith, C H]]
[[Category: Besson, T]]
[[Category: Bountra, C]]
[[Category: Chaikuad, A]]
[[Category: Delft, F von]]
[[Category: Edwards, A]]
[[Category: Knapp, S]]
[[Category: Structural genomic]]
[[Category: Inhibitor]]
[[Category: Kinase]]
[[Category: Sgc]]
[[Category: Transferase]]
[[Category: Unusual binding mode]]