6khe - Revision history

OCA at 10:42, 27 March 2024

OCA — Wed, 27 Mar 2024 10:42:42 GMT

←Older revision		Revision as of 10:42, 27 March 2024
Line 3:		Line 3:
	<StructureSection load='6khe' size='340' side='right'caption='[[6khe]], [[Resolution\|resolution]] 2.80Å' scene=''>		<StructureSection load='6khe' size='340' side='right'caption='[[6khe]], [[Resolution\|resolution]] 2.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6khe]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KHE OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6KHE FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6khe]] is a 1 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=6KHE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KHE FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=3NG:5~~-[~~(3-CHLOROPHENYL)AMINO]BENZO~~[C][2~~,6]NAPHTHYRIDINE-~~8~~-CARBOXYLIC+ACID'>3NG</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]] 2.8Å</td></tr>
-	<tr id='~~activity~~'><td class="sblockLbl"><b>~~Activity~~:</b></td><td class="sblockDat"><~~span class~~='~~plainlinks'>[http~~:~~//en.wikipedia.org/wiki/Dual~~-~~specificity_kinase Dual~~-~~specificity kinase~~]~~, with EC number~~ [~~http://www.brenda-enzymes.info/php/result_flat.php4?ecno=~~2~~.7.12.1 2.7.12.1~~] </~~span~~></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3NG:5-[(3-CHLOROPHENYL)AMINO]BENZO[C][2,6]NAPHTHYRIDINE-8-CARBOXYLIC+ACID'>3NG</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=6khe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6khe OCA], [~~http~~://pdbe.org/6khe PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6khe RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6khe PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6khe ProSAT]</span></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=6khe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6khe OCA], [https://pdbe.org/6khe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6khe RCSB], [https://www.ebi.ac.uk/pdbsum/6khe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6khe ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/CLK2_HUMAN CLK2_HUMAN]] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.<ref>PMID:10480872</ref> <ref>PMID:19168442</ref> <ref>PMID:8910305</ref> <ref>PMID:9637771</ref>	+	[https://www.uniprot.org/uniprot/CLK2_HUMAN CLK2_HUMAN] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.<ref>PMID:10480872</ref> <ref>PMID:19168442</ref> <ref>PMID:8910305</ref> <ref>PMID:9637771</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Cdc2-like kinases (CLKs) play a crucial role in the alternative splicing of eukaryotic pre-mRNAs through the phosphorylation of serine/arginine-rich proteins (SR proteins). Dysregulation of this processes is linked with various diseases including cancers, neurodegenerative diseases, and many genetic diseases. Thus, CLKs have been regarded to have a potential as a therapeutic target and significant efforts have been exerted to discover an effective inhibitor. In particular, the small molecule CX-4945, originally identified as an inhibitor of casein kinase 2 (CK2), was further revealed to have a strong CLK-inhibitory activity. Four isoforms of CLKs (CLK1, CLK2, CLK3, and CLK4) can be inhibited by CX-4945, with the highest inhibitory effect on CLK2. This study aimed to elucidate the structural basis of the selective inhibitory effect of CX-4945 on different isoforms of CLKs. We determined the crystal structures of CLK1, CLK2, and CLK3 in complex with CX-4945 at resolutions of 2.4 A, 2.8 A, and 2.6 A, respectively. Comparative analysis revealed that CX-4945 was bound in the same active site pocket of the CLKs with similar interacting networks. Intriguingly, the active sites of CLK/CX-4945 complex structures had different sizes and electrostatic surface charge distributions. The active site of CLK1 was somewhat narrow and contained a negatively charged patch. CLK3 had a protruded Lys248 residue in the entrance of the active site pocket. In addition, Ala319, equivalent to Val324 (CLK1) and Val326 (CLK2), contributed to the weak hydrophobic interactions with the benzonaphthyridine ring of CX-4945. In contrast, the charge distribution pattern of CLK2 was the weakest, favoring its interactions with benzonaphthyridine ring. Thus, the relatively strong binding affinities of CX-4945 with CLK2 are consistent with its strong inhibitory effect defined in the previous study. These results may provide insights into structure-based drug discovery processes.	+

-	Structural Basis for the Selective Inhibition of Cdc2-Like Kinases by CX-4945.,Lee JY, Yun JS, Kim WK, Chun HS, Jin H, Cho S, Chang JH Biomed Res Int. 2019 Aug 18;2019:6125068. doi: 10.1155/2019/6125068. eCollection , 2019. PMID:31531359<ref>PMID:31531359</ref>	+	==See Also==
-		+	*[[Dual specificity protein kinase 3D structures\|Dual specificity protein kinase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6khe" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Dual-specificity kinase~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Chang~~, J H~~]]	+	[[Category: Chang JH]]
-	[[Category: Jin, H]]	+	[[Category: Jin H]]
-	[[Category: Lee~~, J Y~~]]	+	[[Category: Lee JY]]
-	[[Category: Yun~~, J S]]~~	+	[[Category: Yun JS]]
-	~~[[Category: Alternative splicing]]~~	+
-	~~[[Category: Casein kinase]]~~	+
-	~~[[Category: Cdc2-like kinase]]~~	+
-	~~[[Category: Cx-4945]]~~	+
-	~~[[Category: Splicing]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 10:24, 2 October 2019

OCA — Wed, 02 Oct 2019 10:24:08 GMT

←Older revision		Revision as of 10:24, 2 October 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6khe is ~~ON HOLD~~	+	==Crystal structure of CLK2 in complex with CX-4945==
		+	<StructureSection load='6khe' size='340' side='right'caption='[[6khe]], [[Resolution\|resolution]] 2.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6khe]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KHE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KHE FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3NG:5-[(3-CHLOROPHENYL)AMINO]BENZO[C][2,6]NAPHTHYRIDINE-8-CARBOXYLIC+ACID'>3NG</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </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=6khe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6khe OCA], [http://pdbe.org/6khe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6khe RCSB], [http://www.ebi.ac.uk/pdbsum/6khe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6khe ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/CLK2_HUMAN CLK2_HUMAN]] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex. May be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing and can cause redistribution of SR proteins from speckles to a diffuse nucleoplasmic distribution. Acts as a suppressor of hepatic gluconeogenesis and glucose output by repressing PPARGC1A transcriptional activity on gluconeogenic genes via its phosphorylation. Phosphorylates PPP2R5B thereby stimulating the assembly of PP2A phosphatase with the PPP2R5B-AKT1 complex leading to dephosphorylation of AKT1. Phosphorylates: PTPN1, SRSF1 and SRSF3. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells.<ref>PMID:10480872</ref> <ref>PMID:19168442</ref> <ref>PMID:8910305</ref> <ref>PMID:9637771</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Cdc2-like kinases (CLKs) play a crucial role in the alternative splicing of eukaryotic pre-mRNAs through the phosphorylation of serine/arginine-rich proteins (SR proteins). Dysregulation of this processes is linked with various diseases including cancers, neurodegenerative diseases, and many genetic diseases. Thus, CLKs have been regarded to have a potential as a therapeutic target and significant efforts have been exerted to discover an effective inhibitor. In particular, the small molecule CX-4945, originally identified as an inhibitor of casein kinase 2 (CK2), was further revealed to have a strong CLK-inhibitory activity. Four isoforms of CLKs (CLK1, CLK2, CLK3, and CLK4) can be inhibited by CX-4945, with the highest inhibitory effect on CLK2. This study aimed to elucidate the structural basis of the selective inhibitory effect of CX-4945 on different isoforms of CLKs. We determined the crystal structures of CLK1, CLK2, and CLK3 in complex with CX-4945 at resolutions of 2.4 A, 2.8 A, and 2.6 A, respectively. Comparative analysis revealed that CX-4945 was bound in the same active site pocket of the CLKs with similar interacting networks. Intriguingly, the active sites of CLK/CX-4945 complex structures had different sizes and electrostatic surface charge distributions. The active site of CLK1 was somewhat narrow and contained a negatively charged patch. CLK3 had a protruded Lys248 residue in the entrance of the active site pocket. In addition, Ala319, equivalent to Val324 (CLK1) and Val326 (CLK2), contributed to the weak hydrophobic interactions with the benzonaphthyridine ring of CX-4945. In contrast, the charge distribution pattern of CLK2 was the weakest, favoring its interactions with benzonaphthyridine ring. Thus, the relatively strong binding affinities of CX-4945 with CLK2 are consistent with its strong inhibitory effect defined in the previous study. These results may provide insights into structure-based drug discovery processes.

-	~~Authors: Lee, J.Y~~., Yun, ~~J.S.~~, ~~Jin~~, H., ~~Chang~~, J.H.	+	Structural Basis for the Selective Inhibition of Cdc2-Like Kinases by CX-4945.,Lee JY, Yun JS, Kim WK, Chun HS, Jin H, Cho S, Chang JH Biomed Res Int. 2019 Aug 18;2019:6125068. doi: 10.1155/2019/6125068. eCollection , 2019. PMID:31531359<ref>PMID:31531359</ref>

-	~~Description: Crystal structure~~ of ~~CLK2 in complex with CX~~-~~4945~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6khe" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Dual-specificity kinase]]
		+	[[Category: Large Structures]]
		+	[[Category: Chang, J H]]
	[[Category: Jin, H]]		[[Category: Jin, H]]
-	[[Category: ~~Yun~~, J.S]]	+	[[Category: Lee, J Y]]
-	[[Category: ~~Lee~~, J.Y]]	+	[[Category: Yun, J S]]
-	[[Category: ~~Chang, J.H~~]]	+	[[Category: Alternative splicing]]
		+	[[Category: Casein kinase]]
		+	[[Category: Cdc2-like kinase]]
		+	[[Category: Cx-4945]]
		+	[[Category: Splicing]]
		+	[[Category: Transferase]]

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

OCA — Wed, 24 Jul 2019 04:14:20 GMT

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

←Older revision

Revision as of 04:14, 24 July 2019

OCA: New page: '''Unreleased structure''' The entry 6khe is ON HOLD Authors: Lee, J.Y., Yun, J.S., Jin, H., Chang, J.H. Description: Crystal structure of CLK2 in complex with CX-4945 [[Category: Unre...

OCA — Wed, 24 Jul 2019 04:14:19 GMT

New page: '''Unreleased structure''' The entry 6khe is ON HOLD Authors: Lee, J.Y., Yun, J.S., Jin, H., Chang, J.H. Description: Crystal structure of CLK2 in complex with CX-4945 [[Category: Unre...

New page

'''Unreleased structure'''

The entry 6khe is ON HOLD

Authors: Lee, J.Y., Yun, J.S., Jin, H., Chang, J.H.

Description: Crystal structure of CLK2 in complex with CX-4945
[[Category: Unreleased Structures]]
[[Category: Jin, H]]
[[Category: Yun, J.S]]
[[Category: Lee, J.Y]]
[[Category: Chang, J.H]]