5ops - Revision history

OCA at 16:57, 13 December 2023

2023-12-13T16:57:43Z

←Older revision		Revision as of 16:57, 13 December 2023
Line 1:		Line 1:

	==Structure of CHK1 10-pt. mutant complex with pyrrolopyridine LRRK2 inhibitor==		==Structure of CHK1 10-pt. mutant complex with pyrrolopyridine LRRK2 inhibitor==
-	<StructureSection load='5ops' size='340' side='right' caption='[[5ops]], [[Resolution\|resolution]] 2.00Å' scene=''>	+	<StructureSection load='5ops' size='340' side='right'caption='[[5ops]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ops]] 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=5OPS OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5OPS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ops]] 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=5OPS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OPS FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name='pdbligand=A3Q:4-(3-hydroxyphenyl)-1~{H}-pyrrolo[2,3-b]pyridine-3-carbonitrile'>A3Q</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]] 2Å</td></tr>
-	~~<tr~~ id~~='related'><td class~~="~~sblockLbl~~">~~<b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5oop\|5oop]]~~, [[~~5oor~~\|~~5oor]], [[5oot\|5oot]], [[5op2\|5op2]], [[5op4\|5op4]], [[5op5\|5op5]], [[5op7\|5op7]], [[5opb\|5opb]], [[5opr\|5opr~~]]</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A3Q:4-(3-hydroxyphenyl)-1~{H}-pyrrolo[2,3-b]pyridine-3-carbonitrile'>A3Q</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ops FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ops OCA], [https://pdbe.org/5ops PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ops RCSB], [https://www.ebi.ac.uk/pdbsum/5ops PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ops ProSAT]</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=5ops FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ops OCA], [~~http~~://pdbe.org/5ops PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5ops RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5ops PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5ops 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 21:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5ops" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5ops" 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: Homo sapiens]]
-	[[Category: ~~Non-specific serine/threonine protein kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Acheson-Dossang, P]]	+	[[Category: Acheson-Dossang P]]
-	[[Category: Chen, I]]	+	[[Category: Chen I]]
-	[[Category: Dokurno, P]]	+	[[Category: Dokurno P]]
-	[[Category: Murray~~, J B~~]]	+	[[Category: Murray JB]]
-	[[Category: Shaw, T]]	+	[[Category: Shaw T]]
-	[[Category: Surgenor~~, A E~~]]	+	[[Category: Surgenor AE]]
-	[[Category: Williamson~~, D S]]~~	+	[[Category: Williamson DS]]
-	~~[[Category: Checkpoint kinase 1]]~~	+
-	~~[[Category: Chk1]]~~	+
-	~~[[Category: Kinase inhibitor]]~~	+
-	~~[[Category: Leucine-rich repeat kinase 2]]~~	+
-	~~[[Category: Lrrk2]]~~	+
-	~~[[Category: Mutant]]~~	+
-	~~[[Category: Parkinson's disease]]~~	+
-	~~[[Category: Surrogate]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 10:10, 22 November 2017

2017-11-22T10:10:59Z

←Older revision		Revision as of 10:10, 22 November 2017
Line 3:		Line 3:
	<StructureSection load='5ops' size='340' side='right' caption='[[5ops]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='5ops' size='340' side='right' caption='[[5ops]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ops]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OPS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OPS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ops]] 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=5OPS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OPS FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A3Q:4-(3-hydroxyphenyl)-1~{H}-pyrrolo[2,3-b]pyridine-3-carbonitrile'>A3Q</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A3Q:4-(3-hydroxyphenyl)-1~{H}-pyrrolo[2,3-b]pyridine-3-carbonitrile'>A3Q</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5oop\|5oop]], [[5oor\|5oor]], [[5oot\|5oot]], [[5op2\|5op2]], [[5op4\|5op4]], [[5op5\|5op5]], [[5op7\|5op7]], [[5opb\|5opb]], [[5opr\|5opr]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5oop\|5oop]], [[5oor\|5oor]], [[5oot\|5oot]], [[5op2\|5op2]], [[5op4\|5op4]], [[5op5\|5op5]], [[5op7\|5op7]], [[5opb\|5opb]], [[5opr\|5opr]]</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=5ops FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ops OCA], [http://pdbe.org/5ops PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ops RCSB], [http://www.ebi.ac.uk/pdbsum/5ops PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ops 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=5ops FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ops OCA], [http://pdbe.org/5ops PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ops RCSB], [http://www.ebi.ac.uk/pdbsum/5ops PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ops ProSAT]</span></td></tr>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Acheson-Dossang, P]]		[[Category: Acheson-Dossang, P]]

OCA at 06:53, 25 October 2017

2017-10-25T06:53:46Z

←Older revision		Revision as of 06:53, 25 October 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5ops is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Structure of CHK1 10-pt. mutant complex with pyrrolopyridine LRRK2 inhibitor==
		+	<StructureSection load='5ops' size='340' side='right' caption='[[5ops]], [[Resolution\|resolution]] 2.00Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5ops]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OPS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OPS FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A3Q:4-(3-hydroxyphenyl)-1~{H}-pyrrolo[2,3-b]pyridine-3-carbonitrile'>A3Q</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5oop\|5oop]], [[5oor\|5oor]], [[5oot\|5oot]], [[5op2\|5op2]], [[5op4\|5op4]], [[5op5\|5op5]], [[5op7\|5op7]], [[5opb\|5opb]], [[5opr\|5opr]]</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=5ops FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ops OCA], [http://pdbe.org/5ops PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ops RCSB], [http://www.ebi.ac.uk/pdbsum/5ops PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ops ProSAT]</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 ==
		+	Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]-pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC50 data for 22 were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-pt. mut. structure). Compound 22 was shown to be potent, moderately selective, orally available and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC50 values for 22 in mouse brain and kidney being 1.3 nM and 5 nM, respectively.

-	~~Authors: Dokurno, P~~., Williamson, ~~D.S.~~, Acheson-Dossang, P., Chen, I., Murray, ~~J.B.~~, Shaw, T., Surgenor, A.E.	+	Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1).,Williamson DS, Smith GP, Acheson-Dossang P, Bedford ST, Chell V, Chen IJ, Daechsel JCA, Daniels Z, David L, Dokurno P, Hentzer M, Herzig MC, Hubbard RE, Moore JD, Murray JB, Newland S, Ray SC, Shaw T, Surgenor AE, Terry L, Thirstrup K, Wang Y, Christensen KV J Med Chem. 2017 Oct 12. doi: 10.1021/acs.jmedchem.7b01186. PMID:29023112<ref>PMID:29023112</ref>

-	~~Description: Structure~~ of ~~CHK1 10-pt~~. ~~mutant complex with pyrrolopyridine LRRK2 inhibitor~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category: Unreleased Structures]]~~	+	</div>
-	~~[[Category~~: ~~Shaw, T]]~~	+	<div class="pdbe-citations 5ops" style="background-color:#fffaf0;"></div>
-	~~[[Category: Williamson, D.S]]~~	+	== References ==
-	~~[[Category: Murray, J.B]]~~	+	<references/>
-	~~[[Category: Dokurno, P]]~~	+	__TOC__
-	[[Category: ~~Chen, I~~]]	+	</StructureSection>
		+	[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Acheson-Dossang, P]]		[[Category: Acheson-Dossang, P]]
-	[[Category: Surgenor, A.E]]	+	[[Category: Chen, I]]
		+	[[Category: Dokurno, P]]
		+	[[Category: Murray, J B]]
		+	[[Category: Shaw, T]]
		+	[[Category: Surgenor, A E]]
		+	[[Category: Williamson, D S]]
		+	[[Category: Checkpoint kinase 1]]
		+	[[Category: Chk1]]
		+	[[Category: Kinase inhibitor]]
		+	[[Category: Leucine-rich repeat kinase 2]]
		+	[[Category: Lrrk2]]
		+	[[Category: Mutant]]
		+	[[Category: Parkinson's disease]]
		+	[[Category: Surrogate]]
		+	[[Category: Transferase]]

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

2017-09-27T12:41:28Z

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

←Older revision

Revision as of 12:41, 27 September 2017

OCA: New page: '''Unreleased structure''' The entry 5ops is ON HOLD until Paper Publication Authors: Dokurno, P., Williamson, D.S., Acheson-Dossang, P., Chen, I., Murray, J.B., Shaw, T., Surgenor, A.E...

2017-09-27T12:41:27Z

New page: '''Unreleased structure''' The entry 5ops is ON HOLD until Paper Publication Authors: Dokurno, P., Williamson, D.S., Acheson-Dossang, P., Chen, I., Murray, J.B., Shaw, T., Surgenor, A.E...

New page

'''Unreleased structure'''

The entry 5ops is ON HOLD until Paper Publication

Authors: Dokurno, P., Williamson, D.S., Acheson-Dossang, P., Chen, I., Murray, J.B., Shaw, T., Surgenor, A.E.

Description: Structure of CHK1 10-pt. mutant complex with pyrrolopyridine LRRK2 inhibitor
[[Category: Unreleased Structures]]
[[Category: Shaw, T]]
[[Category: Williamson, D.S]]
[[Category: Murray, J.B]]
[[Category: Dokurno, P]]
[[Category: Chen, I]]
[[Category: Acheson-Dossang, P]]
[[Category: Surgenor, A.E]]