4kb8: Difference between revisions

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 == Structural highlights ==
 <table><tr><td colspan='2'>[[4kb8]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KB8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KB8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1QN:1-{4-[3-(4-FLUOROPHENYL)-1-METHYL-1H-PYRAZOL-4-YL]PYRIDIN-2-YL}-N-METHYLMETHANAMINE'>1QN</scene>, <scene name='pdbligand=1QO:N-BENZYL-4-(PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>1QO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1QN:1-{4-[3-(4-FLUOROPHENYL)-1-METHYL-1H-PYRAZOL-4-YL]PYRIDIN-2-YL}-N-METHYLMETHANAMINE'>1QN</scene>, <scene name='pdbligand=1QO:N-BENZYL-4-(PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>1QO</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'>[https://proteopedia.org/fgij/fg.htm?mol=4kb8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kb8 OCA], [https://pdbe.org/4kb8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kb8 RCSB], [https://www.ebi.ac.uk/pdbsum/4kb8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kb8 ProSAT]</span></td></tr>
 </table>
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 == Function ==
 [https://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 ==
-Casein kinase 1delta (CK1delta) and 1epsilon (CK1epsilon) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1epsilon-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1delta isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1delta and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1delta at sufficient central exposure levels is capable of modulating circadian rhythms.
-Ligand-protein interactions of selective casein kinase 1delta inhibitors.,Mente S, Arnold E, Butler T, Chakrapani S, Chandrasekaran R, Cherry K, Dirico K, Doran A, Fisher K, Galatsis P, Green M, Hayward M, Humphrey J, Knafels J, Li J, Liu S, Marconi M, McDonald S, Ohren J, Paradis V, Sneed B, Walton K, Wager T J Med Chem. 2013 Sep 12;56(17):6819-28. doi: 10.1021/jm4006324. Epub 2013 Aug 28. PMID:23919824<ref>PMID:23919824</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 4kb8" style="background-color:#fffaf0;"></div>
 ==See Also==