OCA at 11:57, 13 March 2019

OCA — Wed, 13 Mar 2019 11:57:01 GMT

←Older revision		Revision as of 11:57, 13 March 2019
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-	'''Unreleased structure'''

-	~~The entry~~ 6f1w is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of human Casein Kinase I delta in complex with compound 31a==
		+	<StructureSection load='6f1w' size='340' side='right'caption='[[6f1w]], [[Resolution\|resolution]] 1.86Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6f1w]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F1W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F1W FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CG5:(9~{R},10~{R},11~{S})-~{N}-[4-[3-(4-fluorophenyl)-5-propan-2-yl-1,2-oxazol-4-yl]pyridin-2-yl]-4-(4-methoxyphenyl)-10,11-bis(oxidanyl)-1,7-diazatricyclo[7.3.0.0^{3,7}]dodeca-3,5-diene-6-carboxamide'>CG5</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=TPO:PHOSPHOTHREONINE'>TPO</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=6f1w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f1w OCA], [http://pdbe.org/6f1w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f1w RCSB], [http://www.ebi.ac.uk/pdbsum/6f1w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f1w ProSAT]</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 report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1delta complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral "ribose-like" pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.

-	~~Authors: Pichlo~~, C., ~~Brunstein~~, E., Baumann, U.	+	Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds.,Luxenburger A, Schmidt D, Ianes C, Pichlo C, Kruger M, von Drathen T, Brunstein E, Gainsford GJ, Baumann U, Knippschild U, Peifer C Molecules. 2019 Mar 1;24(5). pii: molecules24050873. doi:, 10.3390/molecules24050873. PMID:30832206<ref>PMID:30832206</ref>

-	~~Description: Crystal structure~~ of ~~human Casein Kinase I delta in complex with compound 31a~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6f1w" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Baumann, U]]		[[Category: Baumann, U]]
-	[[Category: Pichlo, C]]
	[[Category: Brunstein, E]]		[[Category: Brunstein, E]]
		+	[[Category: Pichlo, C]]
		+	[[Category: Ck1]]
		+	[[Category: Complex]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Transferase]]

OCA at 04:07, 24 October 2018

OCA — Wed, 24 Oct 2018 04:07:06 GMT

←Older revision		Revision as of 04:07, 24 October 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6f1w is ON HOLD	+	The entry 6f1w is ON HOLD until Paper Publication

	Authors: Pichlo, C., Brunstein, E., Baumann, U.		Authors: Pichlo, C., Brunstein, E., Baumann, U.

OCA at 06:10, 6 December 2017

OCA — Wed, 06 Dec 2017 06:10:40 GMT

←Older revision		Revision as of 06:10, 6 December 2017
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6f1w is ON HOLD ~~until sometime in the future~~	+	The entry 6f1w is ON HOLD

	Authors: Pichlo, C., Brunstein, E., Baumann, U.		Authors: Pichlo, C., Brunstein, E., Baumann, U.
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	Description: Crystal structure of human Casein Kinase I delta in complex with compound 31a		Description: Crystal structure of human Casein Kinase I delta in complex with compound 31a
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Pichlo, C]]
	[[Category: Baumann, U]]		[[Category: Baumann, U]]
		+	[[Category: Pichlo, C]]
	[[Category: Brunstein, E]]		[[Category: Brunstein, E]]

OCA: Protected "6f1w" [edit=sysop:move=sysop]

OCA — Wed, 29 Nov 2017 05:16:53 GMT

Protected "6f1w" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:16, 29 November 2017

OCA: New page: '''Unreleased structure''' The entry 6f1w is ON HOLD until sometime in the future Authors: Pichlo, C., Brunstein, E., Baumann, U. Description: Crystal structure of human Casein Kinase ...

OCA — Wed, 29 Nov 2017 05:16:52 GMT

New page: '''Unreleased structure''' The entry 6f1w is ON HOLD until sometime in the future Authors: Pichlo, C., Brunstein, E., Baumann, U. Description: Crystal structure of human Casein Kinase ...

New page

'''Unreleased structure'''

The entry 6f1w is ON HOLD until sometime in the future

Authors: Pichlo, C., Brunstein, E., Baumann, U.

Description: Crystal structure of human Casein Kinase I delta in complex with compound 31a
[[Category: Unreleased Structures]]
[[Category: Pichlo, C]]
[[Category: Baumann, U]]
[[Category: Brunstein, E]]

6f1w - Revision history

OCA at 11:57, 13 March 2019

OCA at 04:07, 24 October 2018

OCA at 06:10, 6 December 2017

OCA: Protected "6f1w" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6f1w is ON HOLD until sometime in the future Authors: Pichlo, C., Brunstein, E., Baumann, U. Description: Crystal structure of human Casein Kinase ...