View source for 7nzy


==Crystal structure of human Casein Kinase I delta in complex with CGS-15943==
<StructureSection load='7nzy' size='340' side='right'caption='[[7nzy]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7nzy]] 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=7NZY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NZY FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=UX2:9-chloranyl-2-(furan-2-yl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine'>UX2</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=7nzy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nzy OCA], [https://pdbe.org/7nzy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nzy RCSB], [https://www.ebi.ac.uk/pdbsum/7nzy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nzy ProSAT]</span></td></tr>
</table>
== Disease ==
[https://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 ==
[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 ==
Phenotypic drug discovery (PDD) continues to fuel the research and development pipelines with first-in-class therapeutic modalities, but success rates critically depend on the quality of the underlying model system. Here, we employed a stem cell-based approach for the target-agnostic, yet pathway-centric discovery of small-molecule cytokine signaling activators to act as morphogens during development and regeneration. Unbiased screening identified triazolo[1,5-c]quinazolines as a new-in-class in vitro and in vivo active amplifier of the bone morphogenetic protein (BMP) pathway. Cellular BMP outputs were stimulated via enhanced and sustained availability of BMP-Smad proteins, strictly dependent on a minimal BMP input. Holistic target deconvolution unveiled a unique mechanism of dual targeting of casein kinase 1 and phosphatidyl inositol 3-kinase isoforms as key effectors for efficient amplification of osteogenic BMP signaling. This work underscores the asset of PDD to discover unrecognized polypharmacology signatures, in this case significantly expanding the chemical and druggable space of BMP modulators.

Phenotypic Discovery of Triazolo[1,5-c]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype.,Wesseler F, Lohmann S, Riege D, Halver J, Roth A, Pichlo C, Weber S, Takamiya M, Muller E, Ketzel J, Flegel J, Gihring A, Rastegar S, Bertrand J, Baumann U, Knippschild U, Peifer C, Sievers S, Waldmann H, Schade D J Med Chem. 2022 Nov 24;65(22):15263-15281. doi: 10.1021/acs.jmedchem.2c01199. , Epub 2022 Nov 8. PMID:36346705<ref>PMID:36346705</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7nzy" style="background-color:#fffaf0;"></div>

==See Also==
*[[Casein kinase 3D structures|Casein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Baumann U]]
[[Category: Pichlo C]]