5ta8 - Revision history

OCA at 14:20, 6 March 2024

OCA — Wed, 06 Mar 2024 14:20:06 GMT

←Older revision		Revision as of 14:20, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='5ta8' size='340' side='right'caption='[[5ta8]], [[Resolution\|resolution]] 2.60Å' scene=''>		<StructureSection load='5ta8' size='340' side='right'caption='[[5ta8]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ta8]] 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=5TA8 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5TA8 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ta8]] 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=5TA8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TA8 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=79C:4-[(9-CYCLOPENTYL-7,7-DIFLUORO-5-METHYL-6-OXO-6,7,8,9-TETRAHYDRO-5H-PYRIMIDO[4,5-B][1,4]DIAZEPIN-2-YL)AMINO]-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>79C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.6Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ta6\|5ta6]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=79C:4-[(9-CYCLOPENTYL-7,7-DIFLUORO-5-METHYL-6-OXO-6,7,8,9-TETRAHYDRO-5H-PYRIMIDO[4,5-B][1,4]DIAZEPIN-2-YL)AMINO]-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>79C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PLK1, PLK ([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=5ta8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta8 OCA], [https://pdbe.org/5ta8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ta8 RCSB], [https://www.ebi.ac.uk/pdbsum/5ta8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta8 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/Polo_kinase Polo kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.21 2.7.11.21] </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=5ta8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta8 OCA], [~~http~~://pdbe.org/5ta8 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5ta8 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5ta8 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta8 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/PLK1_HUMAN PLK1_HUMAN]] Note=Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis.	+	[https://www.uniprot.org/uniprot/PLK1_HUMAN PLK1_HUMAN] Note=Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis.
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PLK1_HUMAN PLK1_HUMAN]] Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, MLF1IP, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, PLK1S1/KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating PLK1S1/KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, MLF1IP, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, MLF1IP, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGOL1: required for spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis.<ref>PMID:8991084</ref> <ref>PMID:11202906</ref> <ref>PMID:12207013</ref> <ref>PMID:12447691</ref> <ref>PMID:12852856</ref> <ref>PMID:12738781</ref> <ref>PMID:12939256</ref> <ref>PMID:12524548</ref> <ref>PMID:14734534</ref> <ref>PMID:15469984</ref> <ref>PMID:15070733</ref> <ref>PMID:15148369</ref> <ref>PMID:16198290</ref> <ref>PMID:16980960</ref> <ref>PMID:16247472</ref> <ref>PMID:17081991</ref> <ref>PMID:17617734</ref> <ref>PMID:17376779</ref> <ref>PMID:17351640</ref> <ref>PMID:18418051</ref> <ref>PMID:18521620</ref> <ref>PMID:18331714</ref> <ref>PMID:18477460</ref> <ref>PMID:18174154</ref> <ref>PMID:19160488</ref> <ref>PMID:18615013</ref> <ref>PMID:19473992</ref> <ref>PMID:19509060</ref> <ref>PMID:19351716</ref> <ref>PMID:19468300</ref> <ref>PMID:19468302</ref> <ref>PMID:14532005</ref> <ref>PMID:19597481</ref>	+	[https://www.uniprot.org/uniprot/PLK1_HUMAN PLK1_HUMAN] Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, MLF1IP, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, PLK1S1/KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating PLK1S1/KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, MLF1IP, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, MLF1IP, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGOL1: required for spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis.<ref>PMID:8991084</ref> <ref>PMID:11202906</ref> <ref>PMID:12207013</ref> <ref>PMID:12447691</ref> <ref>PMID:12852856</ref> <ref>PMID:12738781</ref> <ref>PMID:12939256</ref> <ref>PMID:12524548</ref> <ref>PMID:14734534</ref> <ref>PMID:15469984</ref> <ref>PMID:15070733</ref> <ref>PMID:15148369</ref> <ref>PMID:16198290</ref> <ref>PMID:16980960</ref> <ref>PMID:16247472</ref> <ref>PMID:17081991</ref> <ref>PMID:17617734</ref> <ref>PMID:17376779</ref> <ref>PMID:17351640</ref> <ref>PMID:18418051</ref> <ref>PMID:18521620</ref> <ref>PMID:18331714</ref> <ref>PMID:18477460</ref> <ref>PMID:18174154</ref> <ref>PMID:19160488</ref> <ref>PMID:18615013</ref> <ref>PMID:19473992</ref> <ref>PMID:19509060</ref> <ref>PMID:19351716</ref> <ref>PMID:19468300</ref> <ref>PMID:19468302</ref> <ref>PMID:14532005</ref> <ref>PMID:19597481</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.	+
-		+
-	Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors.,Kiryanov A, Natala S, Jones B, McBride C, Feher V, Lam B, Liu Y, Honda K, Uchiyama N, Kawamoto T, Hikichi Y, Zhang L, Hosfield D, Skene R, Zou H, Stafford J, Cao X, Ichikawa T Bioorg Med Chem Lett. 2017 Mar 1;27(5):1311-1315. doi:, 10.1016/j.bmcl.2016.10.009. Epub 2016 Oct 15. PMID:28169164<ref>PMID:28169164</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5ta8" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 30:		Line 19:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Polo kinase]]~~	+	[[Category: Hosfield DJ]]
-	[[Category: Hosfield~~, D J~~]]	+	[[Category: Skene RJ]]
-	[[Category: Skene~~, R J]]~~	+
-	~~[[Category: Antitumor activity]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Plk1 inhibitor]]~~	+
-	~~[[Category: Structure-based drug design]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 11:28, 16 September 2020

OCA — Wed, 16 Sep 2020 11:28:16 GMT

←Older revision		Revision as of 11:28, 16 September 2020
Line 1:		Line 1:

	==Crystal structure of PLK1 in complex with a novel 5,6-dihydroimidazolo[1,5-f]pteridine inhibitor==		==Crystal structure of PLK1 in complex with a novel 5,6-dihydroimidazolo[1,5-f]pteridine inhibitor==
-	<StructureSection load='5ta8' size='340' side='right' caption='[[5ta8]], [[Resolution\|resolution]] 2.60Å' scene=''>	+	<StructureSection load='5ta8' size='340' side='right'caption='[[5ta8]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ta8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TA8 OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5TA8 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ta8]] 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=5TA8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5TA8 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=79C:4-[(9-CYCLOPENTYL-7,7-DIFLUORO-5-METHYL-6-OXO-6,7,8,9-TETRAHYDRO-5H-PYRIMIDO[4,5-B][1,4]DIAZEPIN-2-YL)AMINO]-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>79C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=79C:4-[(9-CYCLOPENTYL-7,7-DIFLUORO-5-METHYL-6-OXO-6,7,8,9-TETRAHYDRO-5H-PYRIMIDO[4,5-B][1,4]DIAZEPIN-2-YL)AMINO]-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>79C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ta6\|5ta6]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ta6\|5ta6]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PLK1, PLK ([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/Polo_kinase Polo kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.21 2.7.11.21] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Polo_kinase Polo kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.21 2.7.11.21] </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=5ta8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta8 OCA], [http://pdbe.org/5ta8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ta8 RCSB], [http://www.ebi.ac.uk/pdbsum/5ta8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta8 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=5ta8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta8 OCA], [http://pdbe.org/5ta8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ta8 RCSB], [http://www.ebi.ac.uk/pdbsum/5ta8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta8 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 22:		Line 23:
	</div>		</div>
	<div class="pdbe-citations 5ta8" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5ta8" 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: Polo kinase]]		[[Category: Polo kinase]]
	[[Category: Hosfield, D J]]		[[Category: Hosfield, D J]]

OCA at 08:01, 9 March 2017

OCA — Thu, 09 Mar 2017 08:01:41 GMT

←Older revision		Revision as of 08:01, 9 March 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5ta8 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of PLK1 in complex with a novel 5,6-dihydroimidazolo[1,5-f]pteridine inhibitor==
		+	<StructureSection load='5ta8' size='340' side='right' caption='[[5ta8]], [[Resolution\|resolution]] 2.60Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5ta8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TA8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TA8 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=79C:4-[(9-CYCLOPENTYL-7,7-DIFLUORO-5-METHYL-6-OXO-6,7,8,9-TETRAHYDRO-5H-PYRIMIDO[4,5-B][1,4]DIAZEPIN-2-YL)AMINO]-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>79C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5ta6\|5ta6]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Polo_kinase Polo kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.21 2.7.11.21] </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=5ta8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta8 OCA], [http://pdbe.org/5ta8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ta8 RCSB], [http://www.ebi.ac.uk/pdbsum/5ta8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta8 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/PLK1_HUMAN PLK1_HUMAN]] Note=Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PLK1_HUMAN PLK1_HUMAN]] Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, MLF1IP, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, PLK1S1/KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating PLK1S1/KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, MLF1IP, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, MLF1IP, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGOL1: required for spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis.<ref>PMID:8991084</ref> <ref>PMID:11202906</ref> <ref>PMID:12207013</ref> <ref>PMID:12447691</ref> <ref>PMID:12852856</ref> <ref>PMID:12738781</ref> <ref>PMID:12939256</ref> <ref>PMID:12524548</ref> <ref>PMID:14734534</ref> <ref>PMID:15469984</ref> <ref>PMID:15070733</ref> <ref>PMID:15148369</ref> <ref>PMID:16198290</ref> <ref>PMID:16980960</ref> <ref>PMID:16247472</ref> <ref>PMID:17081991</ref> <ref>PMID:17617734</ref> <ref>PMID:17376779</ref> <ref>PMID:17351640</ref> <ref>PMID:18418051</ref> <ref>PMID:18521620</ref> <ref>PMID:18331714</ref> <ref>PMID:18477460</ref> <ref>PMID:18174154</ref> <ref>PMID:19160488</ref> <ref>PMID:18615013</ref> <ref>PMID:19473992</ref> <ref>PMID:19509060</ref> <ref>PMID:19351716</ref> <ref>PMID:19468300</ref> <ref>PMID:19468302</ref> <ref>PMID:14532005</ref> <ref>PMID:19597481</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.

-	~~Authors: Skene~~, ~~R.J~~., ~~Hosfield~~, D.J.	+	Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors.,Kiryanov A, Natala S, Jones B, McBride C, Feher V, Lam B, Liu Y, Honda K, Uchiyama N, Kawamoto T, Hikichi Y, Zhang L, Hosfield D, Skene R, Zou H, Stafford J, Cao X, Ichikawa T Bioorg Med Chem Lett. 2017 Mar 1;27(5):1311-1315. doi:, 10.1016/j.bmcl.2016.10.009. Epub 2016 Oct 15. PMID:28169164<ref>PMID:28169164</ref>

-	~~Description: Crystal structure of PLK1 in complex with a novel 5~~,6-~~dihydroimidazolo[1,5~~-~~f]pteridine inhibitor~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: Hosfield, D.J]]	+	<div class="pdbe-citations 5ta8" style="background-color:#fffaf0;"></div>
-	[[Category: Skene, R.J]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Polo kinase]]
		+	[[Category: Hosfield, D J]]
		+	[[Category: Skene, R J]]
		+	[[Category: Antitumor activity]]
		+	[[Category: Kinase]]
		+	[[Category: Plk1 inhibitor]]
		+	[[Category: Structure-based drug design]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 16:52, 26 October 2016

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	Authors: Skene, R.J., Hosfield, D.J.		Authors: Skene, R.J., Hosfield, D.J.

OCA: Protected "5ta8" [edit=sysop:move=sysop]

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Protected "5ta8" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:25, 21 September 2016

OCA: New page: '''Unreleased structure''' The entry 5ta8 is ON HOLD Authors: Skene, R.J., Hosfield, D.J. Description: Crystal structure of PLK1 in complex with a novel 5,6-dihydroimidazolo[1,5-f]pter...

OCA — Wed, 21 Sep 2016 12:25:07 GMT

New page: '''Unreleased structure''' The entry 5ta8 is ON HOLD Authors: Skene, R.J., Hosfield, D.J. Description: Crystal structure of PLK1 in complex with a novel 5,6-dihydroimidazolo[1,5-f]pter...

New page

'''Unreleased structure'''

The entry 5ta8 is ON HOLD

Authors: Skene, R.J., Hosfield, D.J.

Description: Crystal structure of PLK1 in complex with a novel 5,6-dihydroimidazolo[1,5-f]pteridine inhibitor
[[Category: Unreleased Structures]]
[[Category: Hosfield, D.J]]
[[Category: Skene, R.J]]