5dls - Revision history

OCA at 21:48, 28 June 2023

2023-06-28T21:48:28Z

←Older revision		Revision as of 21:48, 28 June 2023
Line 3:		Line 3:
	<StructureSection load='5dls' size='340' side='right'caption='[[5dls]], [[Resolution\|resolution]] 2.15Å' scene=''>		<StructureSection load='5dls' size='340' side='right'caption='[[5dls]], [[Resolution\|resolution]] 2.15Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5dls]] is a 1 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=5DLS OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5DLS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5dls]] 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=5DLS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DLS FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5CV:1-BENZYL-N-(5-{5-[3-(DIMETHYLAMINO)-2,2-DIMETHYLPROPOXY]-1H-INDOL-2-YL}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)-1H-PYRAZOLE-4-CARBOXAMIDE'>5CV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.15Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CHEK1, CHK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5CV:1-BENZYL-N-(5-{5-[3-(DIMETHYLAMINO)-2,2-DIMETHYLPROPOXY]-1H-INDOL-2-YL}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)-1H-PYRAZOLE-4-CARBOXAMIDE'>5CV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5dls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dls OCA], [https://pdbe.org/5dls PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dls RCSB], [https://www.ebi.ac.uk/pdbsum/5dls PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dls ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5dls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dls OCA], [~~http~~://pdbe.org/5dls PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5dls RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5dls PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5dls ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/CHK1_HUMAN CHK1_HUMAN]] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref> Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref>	+	[https://www.uniprot.org/uniprot/CHK1_HUMAN CHK1_HUMAN] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref> Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 27:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Baker LM]]
-	[[Category: Baker~~, L M~~]]	+	[[Category: Bedford S]]
-	[[Category: Bedford, S]]	+	[[Category: Browne H]]
-	[[Category: Browne, H]]	+	[[Category: Christie M]]
-	[[Category: Christie, M]]	+	[[Category: Drysdale MJ]]
-	[[Category: Drysdale~~, M J~~]]	+	[[Category: Fallowfield M]]
-	[[Category: Fallowfield, M]]	+	[[Category: Fiumana A]]
-	[[Category: Fiumana, A]]	+	[[Category: Foloppe N]]
-	[[Category: Foloppe, N]]	+	[[Category: Massey AJ]]
-	[[Category: Massey~~, A J~~]]	+	[[Category: Scrace S]]
-	[[Category: Scrace, S]]	+	[[Category: Stokes S]]
-	[[Category: Stokes, S]]	+	[[Category: Webb P]]
-	[[Category: Webb, P]]	+	[[Category: Wood M]]
-	[[Category: Wood, M]]	+
-	~~[[Category: Chk1]]~~	+
-	~~[[Category: Fragment]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: V158411~~]]	+

OCA at 08:09, 8 April 2020

2020-04-08T08:09:24Z

←Older revision		Revision as of 08:09, 8 April 2020
Line 1:		Line 1:
		+
	==Identification of Novel, in vivo Active Chk1 Inhibitors Utilizing Structure Guided Drug Design==		==Identification of Novel, in vivo Active Chk1 Inhibitors Utilizing Structure Guided Drug Design==
-	<StructureSection load='5dls' size='340' side='right' caption='[[5dls]], [[Resolution\|resolution]] 2.15Å' scene=''>	+	<StructureSection load='5dls' size='340' side='right'caption='[[5dls]], [[Resolution\|resolution]] 2.15Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5dls]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DLS OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5DLS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5dls]] is a 1 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=5DLS OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DLS FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5CV:1-BENZYL-N-(5-{5-[3-(DIMETHYLAMINO)-2,2-DIMETHYLPROPOXY]-1H-INDOL-2-YL}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)-1H-PYRAZOLE-4-CARBOXAMIDE'>5CV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5CV:1-BENZYL-N-(5-{5-[3-(DIMETHYLAMINO)-2,2-DIMETHYLPROPOXY]-1H-INDOL-2-YL}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)-1H-PYRAZOLE-4-CARBOXAMIDE'>5CV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CHEK1, CHK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5dls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dls OCA], [http://pdbe.org/5dls PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dls RCSB], [http://www.ebi.ac.uk/pdbsum/5dls PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5dls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dls OCA], [http://pdbe.org/5dls PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dls RCSB], [http://www.ebi.ac.uk/pdbsum/5dls PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dls ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 5dls" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5dls" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Baker, L M]]		[[Category: Baker, L M]]

OCA at 03:54, 16 October 2015

2015-10-16T03:54:30Z

←Older revision		Revision as of 03:54, 16 October 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Identification of Novel, in vivo Active Chk1 Inhibitors Utilizing Structure Guided Drug Design==
		+	<StructureSection load='5dls' size='340' side='right' caption='[[5dls]], [[Resolution\|resolution]] 2.15Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5dls]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DLS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DLS FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5CV:1-BENZYL-N-(5-{5-[3-(DIMETHYLAMINO)-2,2-DIMETHYLPROPOXY]-1H-INDOL-2-YL}-6-OXO-1,6-DIHYDROPYRIDIN-3-YL)-1H-PYRAZOLE-4-CARBOXAMIDE'>5CV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5dls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dls OCA], [http://pdbe.org/5dls PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dls RCSB], [http://www.ebi.ac.uk/pdbsum/5dls PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/CHK1_HUMAN CHK1_HUMAN]] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref> Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation.

-	~~The entry 5dls is ON HOLD until Paper Publication~~	+	Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design.,Massey AJ, Stokes S, Browne H, Foloppe N, Fiumana A, Scrace S, Fallowfield M, Bedford S, Webb P, Baker L, Christie M, Drysdale MJ, Wood M Oncotarget. 2015 Sep 30. PMID:26437226<ref>PMID:26437226</ref>

-	~~Authors: Massey~~, A.~~J., Stokes,~~ S.~~, Browne, H., Foloppe, N., Fiumana, A., Scrace, S., Fallowfield, M., Bedford, S., Webb, P., Baker, L.M., Christie, M., Drysdale, M.J., Wood, M~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Identification of Novel, in vivo Active Chk1 Inhibitors Utilizing Structure Guided Drug Design~~	+	<div class="pdbe-citations 5dls" style="background-color:#fffaf0;"></div>
-	~~[[Category: Unreleased Structures]]~~	+	== References ==
-	~~[[Category: Fiumana, A]]~~	+	<references/>
-	~~[[Category: Massey, A.J]]~~	+	__TOC__
-	[[Category: ~~Stokes, S~~]]	+	</StructureSection>
-	[[Category: ~~Wood~~, M]]	+	[[Category: Non-specific serine/threonine protein kinase]]
-	~~[[Category: Scrace, S~~]]	+	[[Category: Baker, L M]]
	[[Category: Bedford, S]]		[[Category: Bedford, S]]
-	[[Category: ~~Webb~~, ~~P]]~~	+	[[Category: Browne, H]]
-	~~[[Category: Baker, L.M~~]]	+
	[[Category: Christie, M]]		[[Category: Christie, M]]
-	[[Category: ~~Browne~~, H]]	+	[[Category: Drysdale, M J]]
	[[Category: Fallowfield, M]]		[[Category: Fallowfield, M]]
		+	[[Category: Fiumana, A]]
	[[Category: Foloppe, N]]		[[Category: Foloppe, N]]
-	[[Category: ~~Drysdale~~, M.J]]	+	[[Category: Massey, A J]]
		+	[[Category: Scrace, S]]
		+	[[Category: Stokes, S]]
		+	[[Category: Webb, P]]
		+	[[Category: Wood, M]]
		+	[[Category: Chk1]]
		+	[[Category: Fragment]]
		+	[[Category: Kinase]]
		+	[[Category: Transferase]]
		+	[[Category: V158411]]

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

2015-09-30T13:08:34Z

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

←Older revision

Revision as of 13:08, 30 September 2015

OCA: New page: '''Unreleased structure''' The entry 5dls is ON HOLD until Paper Publication Authors: Massey, A.J., Stokes, S., Browne, H., Foloppe, N., Fiumana, A., Scrace, S., Fallowfield, M., Bedfor...

2015-09-30T13:08:32Z

New page: '''Unreleased structure''' The entry 5dls is ON HOLD until Paper Publication Authors: Massey, A.J., Stokes, S., Browne, H., Foloppe, N., Fiumana, A., Scrace, S., Fallowfield, M., Bedfor...

New page

'''Unreleased structure'''

The entry 5dls is ON HOLD until Paper Publication

Authors: Massey, A.J., Stokes, S., Browne, H., Foloppe, N., Fiumana, A., Scrace, S., Fallowfield, M., Bedford, S., Webb, P., Baker, L.M., Christie, M., Drysdale, M.J., Wood, M.

Description: Identification of Novel, in vivo Active Chk1 Inhibitors Utilizing Structure Guided Drug Design
[[Category: Unreleased Structures]]
[[Category: Fiumana, A]]
[[Category: Massey, A.J]]
[[Category: Stokes, S]]
[[Category: Wood, M]]
[[Category: Scrace, S]]
[[Category: Bedford, S]]
[[Category: Webb, P]]
[[Category: Baker, L.M]]
[[Category: Christie, M]]
[[Category: Browne, H]]
[[Category: Fallowfield, M]]
[[Category: Foloppe, N]]
[[Category: Drysdale, M.J]]