4twc: Difference between revisions
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''' | ==2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4- carboxamide derivatives as potent inhibitors of CK1d/e== | ||
<StructureSection load='4twc' size='340' side='right' caption='[[4twc]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4twc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TWC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TWC FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=37J:2-{[2-(TRIFLUOROMETHOXY)BENZOYL]AMINO}-N-[6-(TRIFLUOROMETHYL)-1H-BENZIMIDAZOL-2-YL]-1,3-THIAZOLE-4-CARBOXAMIDE'>37J</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4twc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4twc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4twc RCSB], [http://www.ebi.ac.uk/pdbsum/4twc PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/KC1D_HUMAN KC1D_HUMAN]] Familial advanced sleep-phase syndrome. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/KC1D_HUMAN KC1D_HUMAN]] Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. May act as a negative regulator of circadian rhythmicity by phosphorylating PER1 and PER2, leading to retain PER1 in the cytoplasm. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.<ref>PMID:10606744</ref> <ref>PMID:12270943</ref> <ref>PMID:14761950</ref> <ref>PMID:16027726</ref> <ref>PMID:17962809</ref> <ref>PMID:17562708</ref> <ref>PMID:19043076</ref> <ref>PMID:19339517</ref> <ref>PMID:20637175</ref> <ref>PMID:20041275</ref> <ref>PMID:20048001</ref> <ref>PMID:20699359</ref> <ref>PMID:20696890</ref> <ref>PMID:20407760</ref> <ref>PMID:21084295</ref> <ref>PMID:21422228</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In this study we identified two heterocyclic compounds (5 and 6) as potent and specific inhibitors of CK1delta (IC(50) = 0.040 and 0.042 muM, respectively). Whereas compound 5 exhibited fivefold higher affinity towards CK1delta than to CK1epsilon (IC(50) CK1epsilon = 0.199 muM), compound 6 also inhibited CK1epsilon (IC(50) = 0.0326 muM) in the same range as CK1delta. Selected compound 5 was screened over 442 kinases identifying 5 as a highly potent and selective inhibitor of CK1delta. X-ray analysis of 5 bound to CK1delta demonstrated its binding mode. In addition, characterization of 5 and 6 in a cell biological approach revealed the ability of both compounds to inhibit proliferation of tumor cell lines in a dose and cell line specific manner. In summary, our optimizations lead to the development of new highly selective CK1delta and epsilon specific inhibitors with biological activity. | |||
2-Benzamido-N-(1H-benzo[d]imidazol-2-yl)thiazole-4-carboxamide derivatives as potent inhibitors of CK1delta/epsilon.,Bischof J, Leban J, Zaja M, Grothey A, Radunsky B, Othersen O, Strobl S, Vitt D, Knippschild U Amino Acids. 2012 Oct;43(4):1577-91. Epub 2012 Feb 14. PMID:22331384<ref>PMID:22331384</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bischof, J.]] | |||
[[Category: Grothey, A.]] | |||
[[Category: Knippschild, U.]] | |||
[[Category: Leban, L.]] | |||
[[Category: Othersen, O.]] | |||
[[Category: Radunsky, B.]] | |||
[[Category: Strobl, S.]] | |||
[[Category: Vitt, D.]] | |||
[[Category: Zaja, M.]] | |||
[[Category: Ck1d]] | |||
[[Category: Ck1e]] | |||
[[Category: Phosphorylation]] | |||
[[Category: Small molecule inhibitor]] | |||
[[Category: Transferase]] | |||