5kpk - Revision history

OCA at 10:50, 27 September 2023

OCA — Wed, 27 Sep 2023 10:50:50 GMT

←Older revision		Revision as of 10:50, 27 September 2023
Line 1:		Line 1:

	==Glycogen Synthase Kinase 3 beta Complexed with BRD0209==		==Glycogen Synthase Kinase 3 beta Complexed with BRD0209==
-	<StructureSection load='5kpk' size='340' side='right' caption='[[5kpk]], [[Resolution\|resolution]] 2.40Å' scene=''>	+	<StructureSection load='5kpk' size='340' side='right'caption='[[5kpk]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5kpk]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KPK OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5KPK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5kpk]] 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=5KPK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KPK FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6VK:(4~{S})-3-cyclopropyl-4,7,7-trimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one'>6VK</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]] 2.4Å</td></tr>
-	~~<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>~~</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6VK:(4~{S})-3-cyclopropyl-4,7,7-trimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one'>6VK</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5kpl\|5kpl]], [[5kpm\|5kpm]]</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=5kpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kpk OCA], [https://pdbe.org/5kpk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kpk RCSB], [https://www.ebi.ac.uk/pdbsum/5kpk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kpk ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GSK3B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</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=5kpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kpk OCA], [~~http~~://pdbe.org/5kpk PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5kpk RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5kpk PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5kpk ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://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>	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5kpk" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5kpk" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Glycogen synthase kinase 3 3D structures\|Glycogen synthase kinase 3 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Lakshminarasimhan, D~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Nadupalli, A~~]]	+	[[Category: Lakshminarasimhan D]]
-	[[Category: ~~Suto, R K]]~~	+	[[Category: Nadupalli A]]
-	~~[[Category: White,~~ A]]	+	[[Category: Suto RK]]
-	[[Category: ~~Inhibitor~~]]	+	[[Category: White A]]
-	[[Category: ~~Protein kinase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 07:52, 21 March 2018

OCA — Wed, 21 Mar 2018 07:52:43 GMT

←Older revision		Revision as of 07:52, 21 March 2018
Line 3:		Line 3:
	<StructureSection load='5kpk' size='340' side='right' caption='[[5kpk]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='5kpk' size='340' side='right' caption='[[5kpk]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5kpk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KPK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KPK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5kpk]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KPK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KPK FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6VK:(4~{S})-3-cyclopropyl-4,7,7-trimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one'>6VK</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6VK:(4~{S})-3-cyclopropyl-4,7,7-trimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one'>6VK</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5kpl\|5kpl]], [[5kpm\|5kpm]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5kpl\|5kpl]], [[5kpm\|5kpm]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GSK3B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5kpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kpk OCA], [http://pdbe.org/5kpk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kpk RCSB], [http://www.ebi.ac.uk/pdbsum/5kpk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kpk ProSAT]</span></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=5kpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kpk OCA], [http://pdbe.org/5kpk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kpk RCSB], [http://www.ebi.ac.uk/pdbsum/5kpk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kpk ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[[http://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>		[[http://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 ==
		+	Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3alpha/beta inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent beta-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of beta-catenin are associated with many cancers. Knockdown of GSK3alpha or GSK3beta individually does not increase beta-catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)-competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp(133)-->Glu(196) "switch" in their kinase hinge, we present a rational design strategy toward the discovery of paralog-selective GSK3 inhibitors. These GSK3alpha- and GSK3beta-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3alpha was identified as a therapeutic target using genetic approaches. The GSK3alpha-selective compound BRD0705 inhibits kinase function and does not stabilize beta-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3alpha inhibition, offering a promising therapeutic approach in AML.
		+
		+	Exploiting an Asp-Glu "switch" in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia.,Wagner FF, Benajiba L, Campbell AJ, Weiwer M, Sacher JR, Gale JP, Ross L, Puissant A, Alexe G, Conway A, Back M, Pikman Y, Galinsky I, DeAngelo DJ, Stone RM, Kaya T, Shi X, Robers MB, Machleidt T, Wilkinson J, Hermine O, Kung A, Stein AJ, Lakshminarasimhan D, Hemann MT, Scolnick E, Zhang YL, Pan JQ, Stegmaier K, Holson EB Sci Transl Med. 2018 Mar 7;10(431). pii: 10/431/eaam8460. doi:, 10.1126/scitranslmed.aam8460. PMID:29515000<ref>PMID:29515000</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5kpk" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Lakshminarasimhan, D]]		[[Category: Lakshminarasimhan, D]]
	[[Category: Nadupalli, A]]		[[Category: Nadupalli, A]]

OCA at 06:16, 14 March 2018

OCA — Wed, 14 Mar 2018 06:16:42 GMT

←Older revision		Revision as of 06:16, 14 March 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5kpk is ~~ON HOLD until Mar 28 2019~~	+	==Glycogen Synthase Kinase 3 beta Complexed with BRD0209==
-		+	<StructureSection load='5kpk' size='340' side='right' caption='[[5kpk]], [[Resolution\|resolution]] 2.40Å' scene=''>
-	~~Authors~~: ~~Lakshminarasimhan~~, D., ~~White~~, A., ~~Nadupalli~~, A., ~~Suto, R~~.K.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[5kpk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KPK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KPK FirstGlance]. <br>
-	~~Description~~: ~~Glycogen Synthase Kinase 3~~ beta ~~Complexed~~ with ~~BRD0209~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6VK:(4~{S})-3-cyclopropyl-4,7,7-trimethyl-4-phenyl-2,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one'>6VK</scene></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
-	[[Category: Suto, R.K]]	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5kpl\|5kpl]], [[5kpm\|5kpm]]</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=5kpk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kpk OCA], [http://pdbe.org/5kpk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kpk RCSB], [http://www.ebi.ac.uk/pdbsum/5kpk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kpk ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://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>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Lakshminarasimhan, D]]
		+	[[Category: Nadupalli, A]]
		+	[[Category: Suto, R K]]
	[[Category: White, A]]		[[Category: White, A]]
-	[[Category: ~~Nadupalli, A~~]]	+	[[Category: Inhibitor]]
-	[[Category: ~~Lakshminarasimhan, D~~]]	+	[[Category: Protein kinase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 04:45, 28 February 2018

OCA — Wed, 28 Feb 2018 04:45:17 GMT

←Older revision		Revision as of 04:45, 28 February 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5kpk is ON HOLD until ~~Feb~~ 28 2019	+	The entry 5kpk is ON HOLD until Mar 28 2019

	Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.		Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.

OCA at 04:45, 20 December 2017

OCA — Wed, 20 Dec 2017 04:45:50 GMT

←Older revision		Revision as of 04:45, 20 December 2017
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5kpk is ON HOLD until ~~Jan 10~~ 2019	+	The entry 5kpk is ON HOLD until Feb 28 2019

	Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.		Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.

OCA at 10:48, 27 September 2017

OCA — Wed, 27 Sep 2017 10:48:17 GMT

←Older revision		Revision as of 10:48, 27 September 2017
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5kpk is ON HOLD until ~~Paper Publication~~	+	The entry 5kpk is ON HOLD until Jan 10 2019

	Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.		Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.

OCA at 10:21, 9 March 2017

OCA — Thu, 09 Mar 2017 10:21:48 GMT

←Older revision		Revision as of 10:21, 9 March 2017
Line 7:		Line 7:
	Description: Glycogen Synthase Kinase 3 beta Complexed with BRD0209		Description: Glycogen Synthase Kinase 3 beta Complexed with BRD0209
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
		+	[[Category: Suto, R.K]]
	[[Category: White, A]]		[[Category: White, A]]
	[[Category: Nadupalli, A]]		[[Category: Nadupalli, A]]
	[[Category: Lakshminarasimhan, D]]		[[Category: Lakshminarasimhan, D]]
-	[[Category: Suto, R.K]]

OCA at 13:38, 10 August 2016

OCA — Wed, 10 Aug 2016 13:38:21 GMT

←Older revision		Revision as of 13:38, 10 August 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5kpk is ON HOLD	+	The entry 5kpk is ON HOLD until Paper Publication

	Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.		Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.

OCA: Protected "5kpk" [edit=sysop:move=sysop]

OCA — Thu, 14 Jul 2016 09:33:08 GMT

Protected "5kpk" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:33, 14 July 2016

OCA: New page: '''Unreleased structure''' The entry 5kpk is ON HOLD Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K. Description: Glycogen Synthase Kinase 3 beta Complexed with BR...

OCA — Thu, 14 Jul 2016 09:33:06 GMT

New page: '''Unreleased structure''' The entry 5kpk is ON HOLD Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K. Description: Glycogen Synthase Kinase 3 beta Complexed with BR...

New page

'''Unreleased structure'''

The entry 5kpk is ON HOLD

Authors: Lakshminarasimhan, D., White, A., Nadupalli, A., Suto, R.K.

Description: Glycogen Synthase Kinase 3 beta Complexed with BRD0209
[[Category: Unreleased Structures]]
[[Category: White, A]]
[[Category: Nadupalli, A]]
[[Category: Lakshminarasimhan, D]]
[[Category: Suto, R.K]]