7oy5 - Revision history

OCA at 12:58, 1 February 2024

OCA — Thu, 01 Feb 2024 12:58:30 GMT

←Older revision		Revision as of 12:58, 1 February 2024
Line 1:		Line 1:

	==Crystal structure of GSK3Beta in complex with ARN25068==		==Crystal structure of GSK3Beta in complex with ARN25068==
-	<StructureSection load='7oy5' size='340' side='right'caption='[[7oy5]]' scene=''>	+	<StructureSection load='7oy5' size='340' side='right'caption='[[7oy5]], [[Resolution\|resolution]] 2.57Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OY5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OY5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7oy5]] is a 2 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=7OY5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OY5 FirstGlance]. <br>
-	</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=7oy5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oy5 OCA], [https://pdbe.org/7oy5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oy5 RCSB], [https://www.ebi.ac.uk/pdbsum/7oy5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oy5 ProSAT]</span></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]] 2.57Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=39I:~{N}4-(3-cyclopropyl-1~{H}-pyrazol-5-yl)-~{N}2-(phenylmethyl)thieno[3,2-d]pyrimidine-2,4-diamine'>39I</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=7oy5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oy5 OCA], [https://pdbe.org/7oy5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oy5 RCSB], [https://www.ebi.ac.uk/pdbsum/7oy5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oy5 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/GSK3B_HUMAN GSK3B_HUMAN] Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation.<ref>PMID:1846781</ref> <ref>PMID:8397507</ref> <ref>PMID:9072970</ref> <ref>PMID:9819408</ref> <ref>PMID:11430833</ref> <ref>PMID:14690523</ref> <ref>PMID:15448698</ref> <ref>PMID:18348280</ref> <ref>PMID:20932480</ref> <ref>PMID:20937854</ref> <ref>PMID:22514281</ref> <ref>PMID:12554650</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence has reported the great potential of the simultaneous modulation of multiple protein kinases (PKs) involved in abnormal tau phosphorylation through a concerted pharmacological approach to achieve a superior therapeutic effect relative to classic "one target, one drug" approaches. Here, we report on the identification and characterization of ARN25068 (4), a low nanomolar and well-balanced dual GSK-3beta and FYN inhibitor, which also shows inhibitory activity against DYRK1A, an emerging target in AD and tauopathies. Computational and X-Ray studies highlight compound 4's typical H-bonding pattern of ATP-competitive inhibitors at the binding sites of all three PKs. In a tau phosphorylation assay on Tau0N4R-TM-tGFP U2OS cell line, 4 reduces the extent of tau phosphorylation, promoting tau-stabilized microtubule bundles. In conclusion, this compound emerges as a promising prototype for further SAR explorations to develop potent and well-balanced triple GSK-3beta/FYN/DYRK1A inhibitors to tackle tau hyperphosphorylation.
		+
		+	ARN25068, a versatile starting point towards triple GSK-3beta/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders.,Demuro S, Sauvey C, Tripathi SK, Di Martino RMC, Shi D, Ortega JA, Russo D, Balboni B, Giabbai B, Storici P, Girotto S, Abagyan R, Cavalli A Eur J Med Chem. 2022 Feb 5;229:114054. doi: 10.1016/j.ejmech.2021.114054. Epub, 2021 Dec 16. PMID:34959172<ref>PMID:34959172</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7oy5" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Glycogen synthase kinase 3 3D structures\|Glycogen synthase kinase 3 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Balboni B]]		[[Category: Balboni B]]

OCA at 06:19, 2 March 2022

OCA — Wed, 02 Mar 2022 06:19:21 GMT

←Older revision		Revision as of 06:19, 2 March 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7oy5 ~~is ON HOLD until Paper Publication~~	+	==Crystal structure of GSK3Beta in complex with ARN25068==
-		+	<StructureSection load='7oy5' size='340' side='right'caption='[[7oy5]]' scene=''>
-	~~Authors~~: ~~Tripathi, S~~.K.~~, Balboni, B~~.~~, Demuro, S~~.~~, DiMartino, R~~., ~~Giabbai, B~~., ~~Storici, P~~., ~~Ortega, J~~., ~~Girotto, S~~., ~~Cavalli, A~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OY5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OY5 FirstGlance]. <br>
-	~~Description: Crystal structure of GSK3Beta in complex with ARN25068~~	+	</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=7oy5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oy5 OCA], [https://pdbe.org/7oy5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oy5 RCSB], [https://www.ebi.ac.uk/pdbsum/7oy5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oy5 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Storici, P~~]]	+	__TOC__
-	[[Category: ~~Demuro, S~~]]	+	</StructureSection>
-	[[Category: ~~Girotto,~~ S]]	+	[[Category: Large Structures]]
-	[[Category: ~~Ortega, J~~]]	+	[[Category: Balboni B]]
-	[[Category: ~~Balboni,~~ B]]	+	[[Category: Cavalli A]]
-	[[Category: ~~Dimartino, R~~]]	+	[[Category: Demuro S]]
-	[[Category: ~~Cavalli, A~~]]	+	[[Category: DiMartino R]]
-	[[Category: ~~Tripathi, S.K~~]]	+	[[Category: Giabbai B]]
-	[[Category: ~~Giabbai, B~~]]	+	[[Category: Girotto S]]
		+	[[Category: Ortega J]]
		+	[[Category: Storici P]]
		+	[[Category: Tripathi SK]]

OCA at 08:51, 7 July 2021

OCA — Wed, 07 Jul 2021 08:51:32 GMT

←Older revision		Revision as of 08:51, 7 July 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7oy5 is ON HOLD	+	The entry 7oy5 is ON HOLD until Paper Publication

-	Authors: Tripathi, S.T., Balboni, B., Demuro, S., DiMartino, R., Ortega, J., Girotto, S., Cavalli, A.	+	Authors: Tripathi, S.K., Balboni, B., Demuro, S., DiMartino, R., Giabbai, B., Storici, P., Ortega, J., Girotto, S., Cavalli, A.

	Description: Crystal structure of GSK3Beta in complex with ARN25068		Description: Crystal structure of GSK3Beta in complex with ARN25068
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
		+	[[Category: Storici, P]]
	[[Category: Demuro, S]]		[[Category: Demuro, S]]
-	[[Category: Balboni, B]]
-	[[Category: Dimartino, R]]
	[[Category: Girotto, S]]		[[Category: Girotto, S]]
	[[Category: Ortega, J]]		[[Category: Ortega, J]]
-	[[Category: ~~Tripathi~~, ~~S.T~~]]	+	[[Category: Balboni, B]]
		+	[[Category: Dimartino, R]]
	[[Category: Cavalli, A]]		[[Category: Cavalli, A]]
		+	[[Category: Tripathi, S.K]]
		+	[[Category: Giabbai, B]]

OCA: Protected "7oy5" [edit=sysop:move=sysop]

OCA — Fri, 02 Jul 2021 02:36:40 GMT

Protected "7oy5" [edit=sysop:move=sysop]

←Older revision

Revision as of 02:36, 2 July 2021

OCA: New page: '''Unreleased structure''' The entry 7oy5 is ON HOLD Authors: Tripathi, S.T., Balboni, B., Demuro, S., DiMartino, R., Ortega, J., Girotto, S., Cavalli, A. Description: Crystal structur...

OCA — Fri, 02 Jul 2021 02:36:39 GMT

New page: '''Unreleased structure''' The entry 7oy5 is ON HOLD Authors: Tripathi, S.T., Balboni, B., Demuro, S., DiMartino, R., Ortega, J., Girotto, S., Cavalli, A. Description: Crystal structur...

New page

'''Unreleased structure'''

The entry 7oy5 is ON HOLD

Authors: Tripathi, S.T., Balboni, B., Demuro, S., DiMartino, R., Ortega, J., Girotto, S., Cavalli, A.

Description: Crystal structure of GSK3Beta in complex with ARN25068
[[Category: Unreleased Structures]]
[[Category: Demuro, S]]
[[Category: Balboni, B]]
[[Category: Dimartino, R]]
[[Category: Girotto, S]]
[[Category: Ortega, J]]
[[Category: Tripathi, S.T]]
[[Category: Cavalli, A]]