2ycr - Revision history

OCA at 10:49, 20 December 2023

2023-12-20T10:49:49Z

←Older revision		Revision as of 10:49, 20 December 2023
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	<StructureSection load='2ycr' size='340' side='right'caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='2ycr' size='340' side='right'caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2ycr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YCR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YCR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2ycr]] 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=2YCR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YCR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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]] 2.2Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2wti\|2wti]], [[2xbj\|2xbj]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2ycf\|2ycf]], [[2wtc\|2wtc]], [[2wtj\|2wtj]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2xm8\|2xm8]], [[2wtd\|2wtd]], [[2ycs\|2ycs]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [https://pdbe.org/2ycr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [https://www.ebi.ac.uk/pdbsum/2ycr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ycr 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=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [https://pdbe.org/2ycr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [https://www.ebi.ac.uk/pdbsum/2ycr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ycr ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Defects in CHEK2 are associated with Li-Fraumeni syndrome 2 (LFS2) [MIM:[https://omim.org/entry/609265 609265]]; a highly penetrant familial cancer phenotype usually associated with inherited mutations in p53/TP53.<ref>PMID:11719428</ref> Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:[https://omim.org/entry/176807 176807]]. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Defects in CHEK2 are found in some patients with osteogenic sarcoma (OSRC) [MIM:[https://omim.org/entry/259500 259500]]. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=CHEK2 variants are associated with susceptibility to breast cancer and contribute to a substantial fraction of familial breast cancer (PubMed:12094328).<ref>PMID:12094328</ref> <ref>PMID:21618645</ref>	+	[https://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN] Defects in CHEK2 are associated with Li-Fraumeni syndrome 2 (LFS2) [MIM:[https://omim.org/entry/609265 609265]; a highly penetrant familial cancer phenotype usually associated with inherited mutations in p53/TP53.<ref>PMID:11719428</ref> Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:[https://omim.org/entry/176807 176807]. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Defects in CHEK2 are found in some patients with osteogenic sarcoma (OSRC) [MIM:[https://omim.org/entry/259500 259500]. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=CHEK2 variants are associated with susceptibility to breast cancer and contribute to a substantial fraction of familial breast cancer (PubMed:12094328).<ref>PMID:12094328</ref> <ref>PMID:21618645</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.<ref>PMID:9836640</ref> <ref>PMID:9889122</ref> <ref>PMID:10097108</ref> <ref>PMID:10724175</ref> <ref>PMID:11298456</ref> <ref>PMID:12402044</ref> <ref>PMID:12810724</ref> <ref>PMID:12717439</ref> <ref>PMID:12607004</ref> <ref>PMID:16163388</ref> <ref>PMID:17380128</ref> <ref>PMID:17715138</ref> <ref>PMID:17101782</ref> <ref>PMID:18728393</ref> <ref>PMID:18644861</ref> <ref>PMID:18317453</ref> <ref>PMID:20364141</ref>	+	[https://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.<ref>PMID:9836640</ref> <ref>PMID:9889122</ref> <ref>PMID:10097108</ref> <ref>PMID:10724175</ref> <ref>PMID:11298456</ref> <ref>PMID:12402044</ref> <ref>PMID:12810724</ref> <ref>PMID:12717439</ref> <ref>PMID:12607004</ref> <ref>PMID:16163388</ref> <ref>PMID:17380128</ref> <ref>PMID:17715138</ref> <ref>PMID:17101782</ref> <ref>PMID:18728393</ref> <ref>PMID:18644861</ref> <ref>PMID:18317453</ref> <ref>PMID:20364141</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Jobson AG]]
-	[[Category: Jobson~~, A G~~]]	+	[[Category: Lountos GT]]
-	[[Category: Lountos~~, G T~~]]	+	[[Category: Pommier Y]]
-	[[Category: Pommier, Y]]	+	[[Category: Self CR]]
-	[[Category: Self~~, C R~~]]	+	[[Category: Shoemaker RH]]
-	[[Category: Shoemaker~~, R H~~]]	+	[[Category: Tropea JE]]
-	[[Category: Tropea~~, J E~~]]	+	[[Category: Waugh DS]]
-	[[Category: Waugh~~, D S~~]]	+	[[Category: Zhang G]]
-	[[Category: Zhang, G]]	+
-	~~[[Category: Anticancer drug design]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 12:26, 27 April 2022

2022-04-27T12:26:53Z

OCA at 12:44, 22 July 2020

2020-07-22T12:44:25Z

←Older revision		Revision as of 12:44, 22 July 2020
Line 1:		Line 1:

	==Crystal structure of checkpoint kinase 2 in complex with inhibitor PV976==		==Crystal structure of checkpoint kinase 2 in complex with inhibitor PV976==
-	<StructureSection load='2ycr' size='340' side='right' caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>	+	<StructureSection load='2ycr' size='340' side='right'caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2ycr]] 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=2YCR OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2YCR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2ycr]] 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=2YCR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2YCR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2xbj\|2xbj]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2ycf\|2ycf]], [[2wtc\|2wtc]], [[2wtj\|2wtj]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2xm8\|2xm8]], [[2wtd\|2wtd]], [[2ycs\|2ycs]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2xbj\|2xbj]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2ycf\|2ycf]], [[2wtc\|2wtc]], [[2wtj\|2wtj]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2xm8\|2xm8]], [[2wtd\|2wtd]], [[2ycs\|2ycs]]</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=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [http://pdbe.org/2ycr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [http://www.ebi.ac.uk/pdbsum/2ycr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2ycr 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=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [http://pdbe.org/2ycr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [http://www.ebi.ac.uk/pdbsum/2ycr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2ycr ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 24:		Line 24:

	==See Also==		==See Also==
-	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]	+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 30:		Line 30:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Jobson, A G]]		[[Category: Jobson, A G]]

OCA at 08:56, 10 October 2018

2018-10-10T08:56:10Z

←Older revision		Revision as of 08:56, 10 October 2018
Line 1:		Line 1:

-	==~~CRYSTAL STRUCTURE OF CHECKPOINT KINASE~~ 2 ~~IN COMPLEX WITH INHIBITOR~~ PV976==	+	==Crystal structure of checkpoint kinase 2 in complex with inhibitor PV976==
	<StructureSection load='2ycr' size='340' side='right' caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='2ycr' size='340' side='right' caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==

OCA at 13:08, 5 August 2016

2016-08-05T13:08:21Z

←Older revision		Revision as of 13:08, 5 August 2016
Line 1:		Line 1:
		+
	==CRYSTAL STRUCTURE OF CHECKPOINT KINASE 2 IN COMPLEX WITH INHIBITOR PV976==		==CRYSTAL STRUCTURE OF CHECKPOINT KINASE 2 IN COMPLEX WITH INHIBITOR PV976==
	<StructureSection load='2ycr' size='340' side='right' caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='2ycr' size='340' side='right' caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2ycr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YCR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YCR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2ycr]] 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=2YCR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YCR FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2xbj\|2xbj]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2ycf\|2ycf]], [[2wtc\|2wtc]], [[2wtj\|2wtj]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2xm8\|2xm8]], [[2wtd\|2wtd]], [[2ycs\|2ycs]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2xbj\|2xbj]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2ycf\|2ycf]], [[2wtc\|2wtc]], [[2wtj\|2wtj]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2xm8\|2xm8]], [[2wtd\|2wtd]], [[2ycs\|2ycs]]</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=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [http://www.ebi.ac.uk/pdbsum/2ycr PDBsum]</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=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [http://pdbe.org/2ycr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [http://www.ebi.ac.uk/pdbsum/2ycr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2ycr ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 2ycr" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 27:		Line 29:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Jobson, A G]]		[[Category: Jobson, A G]]

OCA at 13:24, 18 December 2014

2014-12-18T13:24:35Z

←Older revision		Revision as of 13:24, 18 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_2ycr\| PDB=2ycr \| SCENE= }}~~	+	==CRYSTAL STRUCTURE OF CHECKPOINT KINASE 2 IN COMPLEX WITH INHIBITOR PV976==
-	===CRYSTAL STRUCTURE OF CHECKPOINT KINASE 2 IN COMPLEX WITH INHIBITOR PV976===	+	<StructureSection load='2ycr' size='340' side='right' caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>
-	{~~{ABSTRACT_PUBMED_21963792}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[2ycr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YCR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YCR FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2xbj\|2xbj]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2ycf\|2ycf]], [[2wtc\|2wtc]], [[2wtj\|2wtj]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2xm8\|2xm8]], [[2wtd\|2wtd]], [[2ycs\|2ycs]]</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=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [http://www.ebi.ac.uk/pdbsum/2ycr PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Defects in CHEK2 are associated with Li-Fraumeni syndrome 2 (LFS2) [MIM:[http://omim.org/entry/609265 609265]]; a highly penetrant familial cancer phenotype usually associated with inherited mutations in p53/TP53.<ref>PMID:11719428</ref> Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:[http://omim.org/entry/176807 176807]]. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Defects in CHEK2 are found in some patients with osteogenic sarcoma (OSRC) [MIM:[http://omim.org/entry/259500 259500]]. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=CHEK2 variants are associated with susceptibility to breast cancer and contribute to a substantial fraction of familial breast cancer (PubMed:12094328).<ref>PMID:12094328</ref> <ref>PMID:21618645</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.<ref>PMID:9836640</ref> <ref>PMID:9889122</ref> <ref>PMID:10097108</ref> <ref>PMID:10724175</ref> <ref>PMID:11298456</ref> <ref>PMID:12402044</ref> <ref>PMID:12810724</ref> <ref>PMID:12717439</ref> <ref>PMID:12607004</ref> <ref>PMID:16163388</ref> <ref>PMID:17380128</ref> <ref>PMID:17715138</ref> <ref>PMID:17101782</ref> <ref>PMID:18728393</ref> <ref>PMID:18644861</ref> <ref>PMID:18317453</ref> <ref>PMID:20364141</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Chk2 (checkpoint kinase 2) is a serine/threonine kinase that participates in a series of signaling networks responsible for maintaining genomic integrity and responding to DNA damage. The development of selective Chk2 inhibitors has recently attracted much interest as a means of sensitizing cancer cells to current DNA-damaging agents used in the treatment of cancer. Additionally, selective Chk2 inhibitors may reduce p53-mediated apoptosis in normal tissues, thereby helping to mitigate adverse side effects from chemotherapy and radiation. Thus far, relatively few selective inhibitors of Chk2 have been described and none have yet progressed into clinical trials. Here, we report crystal structures of the catalytic domain of Chk2 in complex with a novel series of potent and selective small molecule inhibitors. These compounds exhibit nanomolar potencies and are selective for Chk2 over Chk1. The structures reported here elucidate the binding modes of these inhibitors to Chk2 and provide information that can be exploited for the structure-assisted design of novel chemotherapeutics.

-	~~==Disease==~~	+	Structural characterization of inhibitor complexes with checkpoint kinase 2 (Chk2), a drug target for cancer therapy.,Lountos GT, Jobson AG, Tropea JE, Self CR, Zhang G, Pommier Y, Shoemaker RH, Waugh DS J Struct Biol. 2011 Dec;176(3):292-301. Epub 2011 Sep 22. PMID:21963792<ref>PMID:21963792</ref>
-	~~[[http://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Defects in CHEK2 are associated~~ with ~~Li-Fraumeni syndrome~~ 2 (~~LFS2~~) ~~[MIM:[http://omim.org/entry/609265 609265]];~~ a ~~highly penetrant familial~~ cancer ~~phenotype usually associated with inherited mutations in p53/TP53~~.<ref>PMID:11719428</ref> Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:[http://omim.org/entry/176807 176807]]. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, ~~mucinous carcinoma~~, ~~prostatic ductal carcinoma~~, ~~transitional cell carcinoma~~, ~~squamous cell carcinoma~~, ~~basal cell carcinoma~~, ~~adenoid cystic carcinoma (basaloid)~~, ~~signet-ring cell carcinoma and neuroendocrine carcinoma~~. ~~Defects in CHEK2 are found in some patients with osteogenic sarcoma~~ (~~OSRC~~) ~~[MIM~~:~~[http://omim~~.~~org/entry/259500 259500]]~~. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=CHEK2 variants are associated with susceptibility to breast cancer and contribute to a substantial fraction of familial breast cancer (PubMed:12094328).<ref>PMID:~~12094328</ref>~~<ref>PMID:~~21618645~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Serine~~/~~threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest~~, ~~activation~~ of ~~DNA repair and apoptosis in response to~~ the ~~presence of DNA double-strand breaks~~. ~~May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-~~S~~/T]~~. ~~Regulates cell cycle checkpoint arrest through phosphorylation~~ of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.<~~ref~~>PMID:9836640</ref><ref>PMID:9889122</ref><ref>PMID:10097108</ref><ref>PMID:10724175</ref><ref>PMID:11298456</ref><ref>PMID:12402044</ref><ref>PMID:12810724</ref><ref>PMID:12717439</ref><ref>PMID:12607004</ref><ref>PMID:16163388</ref><ref>PMID:17380128</ref><ref>PMID:17715138</ref><ref>PMID:17101782</ref><ref>PMID:18728393</ref><ref>PMID:18644861</ref><ref>PMID:18317453</ref><ref>PMID:20364141</~~ref~~>	+	</div>

-	==~~About this Structure~~==	+	==See Also==
-	[[~~2ycr]] is a 1 chain structure with sequence from [http://en.wikipedia.org~~/~~wiki~~/~~Homo_sapiens Homo sapiens~~]~~. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YCR OCA~~].	+	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:021963792</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
-	[[Category: Jobson, A G.]]	+	[[Category: Jobson, A G]]
-	[[Category: Lountos, G T.]]	+	[[Category: Lountos, G T]]
-	[[Category: Pommier, Y.]]	+	[[Category: Pommier, Y]]
-	[[Category: Self, C R.]]	+	[[Category: Self, C R]]
-	[[Category: Shoemaker, R H.]]	+	[[Category: Shoemaker, R H]]
-	[[Category: Tropea, J E.]]	+	[[Category: Tropea, J E]]
-	[[Category: Waugh, D S.]]	+	[[Category: Waugh, D S]]
-	[[Category: Zhang, G.]]	+	[[Category: Zhang, G]]
	[[Category: Anticancer drug design]]		[[Category: Anticancer drug design]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 22:52, 24 March 2013

2013-03-24T22:52:10Z

←Older revision		Revision as of 22:52, 24 March 2013
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-	[[Image:2ycr.jpg\|left\|200px]]
-
-	<!--
-	The line below this paragraph, containing "STRUCTURE_2ycr", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_2ycr\| PDB=2ycr \| SCENE= }}		{{STRUCTURE_2ycr\| PDB=2ycr \| SCENE= }}
-
	===CRYSTAL STRUCTURE OF CHECKPOINT KINASE 2 IN COMPLEX WITH INHIBITOR PV976===		===CRYSTAL STRUCTURE OF CHECKPOINT KINASE 2 IN COMPLEX WITH INHIBITOR PV976===
		+	{{ABSTRACT_PUBMED_21963792}}

		+	==Disease==
		+	[[http://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Defects in CHEK2 are associated with Li-Fraumeni syndrome 2 (LFS2) [MIM:[http://omim.org/entry/609265 609265]]; a highly penetrant familial cancer phenotype usually associated with inherited mutations in p53/TP53.<ref>PMID:11719428</ref> Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:[http://omim.org/entry/176807 176807]]. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Defects in CHEK2 are found in some patients with osteogenic sarcoma (OSRC) [MIM:[http://omim.org/entry/259500 259500]]. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=CHEK2 variants are associated with susceptibility to breast cancer and contribute to a substantial fraction of familial breast cancer (PubMed:12094328).<ref>PMID:12094328</ref><ref>PMID:21618645</ref>

-	<!--	+	==Function==
-	~~The line below this paragraph~~, ~~{{ABSTRACT_PUBMED_21963792}}~~, ~~adds~~ the ~~Publication Abstract~~ to the ~~page~~	+	[[http://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.<ref>PMID:9836640</ref><ref>PMID:9889122</ref><ref>PMID:10097108</ref><ref>PMID:10724175</ref><ref>PMID:11298456</ref><ref>PMID:12402044</ref><ref>PMID:12810724</ref><ref>PMID:12717439</ref><ref>PMID:12607004</ref><ref>PMID:16163388</ref><ref>PMID:17380128</ref><ref>PMID:17715138</ref><ref>PMID:17101782</ref><ref>PMID:18728393</ref><ref>PMID:18644861</ref><ref>PMID:18317453</ref><ref>PMID:20364141</ref>
-	(~~as it appears on PubMed~~ at ~~http:~~//~~www~~.~~pubmed~~.~~gov)~~, ~~where 21963792 is~~ the ~~PubMed ID number~~.	+
-	-->	+
-	~~{{ABSTRACT_PUBMED_21963792}}~~	+

	==About this Structure==		==About this Structure==
Line 22:		Line 13:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:021963792</ref><references group="xtra"/>	+	<ref group="xtra">PMID:021963792</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]

OCA at 12:20, 16 November 2011

2011-11-16T12:20:01Z

←Older revision		Revision as of 12:20, 16 November 2011
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:2ycr.jpg\|left\|200px]]

-	The ~~entry 2ycr~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_2ycr", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_2ycr\| PDB=2ycr \| SCENE= }}

-	~~Authors: Lountos, G.T., Jobson, A.G., Tropea, J.E., Self, C.R., Pommier, Y., Shoemaker, R.H., Zhang, G., Waugh, D.S.~~	+	===CRYSTAL STRUCTURE OF CHECKPOINT KINASE 2 IN COMPLEX WITH INHIBITOR PV976===

-	~~Description~~: ~~Crystal~~ structure ~~of checkpoint kinase 2 in complex~~ with ~~inhibitor PV976~~	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_21963792}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 21963792 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_21963792}}
		+
		+	==About this Structure==
		+	[[2ycr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YCR OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:021963792</ref><references group="xtra"/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Jobson, A G.]]
		+	[[Category: Lountos, G T.]]
		+	[[Category: Pommier, Y.]]
		+	[[Category: Self, C R.]]
		+	[[Category: Shoemaker, R H.]]
		+	[[Category: Tropea, J E.]]
		+	[[Category: Waugh, D S.]]
		+	[[Category: Zhang, G.]]
		+	[[Category: Anticancer drug design]]
		+	[[Category: Transferase]]

OCA at 10:09, 21 April 2011

2011-04-21T10:09:14Z

←Older revision		Revision as of 10:09, 21 April 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 2ycr is ON HOLD	+	The entry 2ycr is ON HOLD until Paper Publication

	Authors: Lountos, G.T., Jobson, A.G., Tropea, J.E., Self, C.R., Pommier, Y., Shoemaker, R.H., Zhang, G., Waugh, D.S.		Authors: Lountos, G.T., Jobson, A.G., Tropea, J.E., Self, C.R., Pommier, Y., Shoemaker, R.H., Zhang, G., Waugh, D.S.

	Description: Crystal structure of checkpoint kinase 2 in complex with inhibitor PV976		Description: Crystal structure of checkpoint kinase 2 in complex with inhibitor PV976

OCA: Protected "2ycr" [edit=sysop:move=sysop]

2011-03-23T06:35:11Z

Protected "2ycr" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:35, 23 March 2011

←Older revision		Revision as of 12:26, 27 April 2022
Line 3:		Line 3:
	<StructureSection load='2ycr' size='340' side='right'caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='2ycr' size='340' side='right'caption='[[2ycr]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2ycr]] 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=2YCR OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=2YCR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2ycr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YCR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YCR FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HCW:1,3-BIS{4-[(1E)-N-(4,5-DIHYDRO-1H-IMIDAZOL-2-YL)ETHANEHYDRAZONOYL]PHENYL}UREA'>HCW</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2xbj\|2xbj]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2ycf\|2ycf]], [[2wtc\|2wtc]], [[2wtj\|2wtj]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2xm8\|2xm8]], [[2wtd\|2wtd]], [[2ycs\|2ycs]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2wti\|2wti]], [[2xbj\|2xbj]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2ycf\|2ycf]], [[2wtc\|2wtc]], [[2wtj\|2wtj]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2xm8\|2xm8]], [[2wtd\|2wtd]], [[2ycs\|2ycs]]</div></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'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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~~://proteopedia.org/fgij/fg.htm?mol=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [~~http~~://pdbe.org/2ycr PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/2ycr PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=2ycr 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=2ycr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ycr OCA], [https://pdbe.org/2ycr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ycr RCSB], [https://www.ebi.ac.uk/pdbsum/2ycr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ycr ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Defects in CHEK2 are associated with Li-Fraumeni syndrome 2 (LFS2) [MIM:[~~http~~://omim.org/entry/609265 609265]]; a highly penetrant familial cancer phenotype usually associated with inherited mutations in p53/TP53.<ref>PMID:11719428</ref> Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:[~~http~~://omim.org/entry/176807 176807]]. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Defects in CHEK2 are found in some patients with osteogenic sarcoma (OSRC) [MIM:[~~http~~://omim.org/entry/259500 259500]]. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:[~~http~~://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=CHEK2 variants are associated with susceptibility to breast cancer and contribute to a substantial fraction of familial breast cancer (PubMed:12094328).<ref>PMID:12094328</ref> <ref>PMID:21618645</ref>	+	[[https://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Defects in CHEK2 are associated with Li-Fraumeni syndrome 2 (LFS2) [MIM:[https://omim.org/entry/609265 609265]]; a highly penetrant familial cancer phenotype usually associated with inherited mutations in p53/TP53.<ref>PMID:11719428</ref> Defects in CHEK2 may be a cause of susceptibility to prostate cancer (PC) [MIM:[https://omim.org/entry/176807 176807]]. It is a malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Defects in CHEK2 are found in some patients with osteogenic sarcoma (OSRC) [MIM:[https://omim.org/entry/259500 259500]]. Defects in CHEK2 is a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Note=CHEK2 variants are associated with susceptibility to breast cancer and contribute to a substantial fraction of familial breast cancer (PubMed:12094328).<ref>PMID:12094328</ref> <ref>PMID:21618645</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.<ref>PMID:9836640</ref> <ref>PMID:9889122</ref> <ref>PMID:10097108</ref> <ref>PMID:10724175</ref> <ref>PMID:11298456</ref> <ref>PMID:12402044</ref> <ref>PMID:12810724</ref> <ref>PMID:12717439</ref> <ref>PMID:12607004</ref> <ref>PMID:16163388</ref> <ref>PMID:17380128</ref> <ref>PMID:17715138</ref> <ref>PMID:17101782</ref> <ref>PMID:18728393</ref> <ref>PMID:18644861</ref> <ref>PMID:18317453</ref> <ref>PMID:20364141</ref>	+	[[https://www.uniprot.org/uniprot/CHK2_HUMAN CHK2_HUMAN]] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells.<ref>PMID:9836640</ref> <ref>PMID:9889122</ref> <ref>PMID:10097108</ref> <ref>PMID:10724175</ref> <ref>PMID:11298456</ref> <ref>PMID:12402044</ref> <ref>PMID:12810724</ref> <ref>PMID:12717439</ref> <ref>PMID:12607004</ref> <ref>PMID:16163388</ref> <ref>PMID:17380128</ref> <ref>PMID:17715138</ref> <ref>PMID:17101782</ref> <ref>PMID:18728393</ref> <ref>PMID:18644861</ref> <ref>PMID:18317453</ref> <ref>PMID:20364141</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==