4bdh - Revision history

OCA at 11:48, 20 December 2023

2023-12-20T11:48:38Z

←Older revision		Revision as of 11:48, 20 December 2023
Line 3:		Line 3:
	<StructureSection load='4bdh' size='340' side='right'caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='4bdh' size='340' side='right'caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BDH FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BDH FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=WVI:3-METHYL-4-(THIOPHEN-2-YL)-1H-PYRAZOL-5-AMINE'>WVI</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]] 2.7Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2w7x\|2w7x]], [[2wtc\|2wtc]], [[2wtd\|2wtd]], [[2wti\|2wti]], [[2wtj\|2wtj]], [[2xbj\|2xbj]], [[2xk9\|2xk9]], [[2xm8\|2xm8]], [[2xm9\|2xm9]], [[2ycf\|2ycf]], [[2ycq\|2ycq]], [[2ycr\|2ycr]], [[2ycs\|2ycs]], [[2yiq\|2yiq]], [[2yir\|2yir]], [[2yit\|2yit]], [[4a9r\|4a9r]], [[4a9s\|4a9s]], [[4a9t\|4a9t]], [[4a9u\|4a9u]], [[4bda\|4bda]], [[4bdb\|4bdb]], [[4bdc\|4bdc]], [[4bdd\|4bdd]], [[4bde\|4bde]], [[4bdf\|4bdf]], [[4bdg\|4bdg]], [[4bdi\|4bdi]], [[4bdj\|4bdj]], [[4bdk\|4bdk]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=WVI:3-METHYL-4-(THIOPHEN-2-YL)-1H-PYRAZOL-5-AMINE'>WVI</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=4bdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bdh OCA], [https://pdbe.org/4bdh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bdh RCSB], [https://www.ebi.ac.uk/pdbsum/4bdh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bdh 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=4bdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bdh OCA], [https://pdbe.org/4bdh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bdh RCSB], [https://www.ebi.ac.uk/pdbsum/4bdh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bdh 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: Aherne GW]]
-	[[Category: Aherne~~, G W~~]]	+	[[Category: Barrie E]]
-	[[Category: Barrie, E]]	+	[[Category: Blagg J]]
-	[[Category: Blagg, J]]	+	[[Category: Boxall K]]
-	[[Category: Boxall, K]]	+	[[Category: Brown N]]
-	[[Category: Brown, N]]	+	[[Category: Burke R]]
-	[[Category: Burke, R]]	+	[[Category: Collins I]]
-	[[Category: Collins, I]]	+	[[Category: Garrett MD]]
-	[[Category: Garrett~~, M D~~]]	+	[[Category: Hoelder S]]
-	[[Category: Hoelder, S]]	+	[[Category: Jones K]]
-	[[Category: Jones, K]]	+	[[Category: McAndrew C]]
-	[[Category: McAndrew, C]]	+	[[Category: Mirza A]]
-	[[Category: Mirza, A]]	+	[[Category: Oliver AW]]
-	~~[[Category: Montfort, R L.M van~~]]	+	[[Category: Peacock S]]
-	[[Category: Oliver~~, A W~~]]	+	[[Category: Richards M]]
-	[[Category: Peacock, S]]	+	[[Category: Silva-Santisteban MC]]
-	[[Category: Richards, M]]	+	[[Category: Westwood IM]]
-	[[Category: Silva-Santisteban~~, M C~~]]	+	[[Category: Van Montfort RLM]]
-	[[Category: Westwood~~, I M~~]]	+
-	[[Category: ~~Transferase~~]]	+

OCA at 07:09, 31 August 2022

2022-08-31T07:09:24Z

←Older revision		Revision as of 07:09, 31 August 2022
Line 3:		Line 3:
	<StructureSection load='4bdh' size='340' side='right'caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='4bdh' size='340' side='right'caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4BDH FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BDH FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=WVI:3-METHYL-4-(THIOPHEN-2-YL)-1H-PYRAZOL-5-AMINE'>WVI</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=WVI:3-METHYL-4-(THIOPHEN-2-YL)-1H-PYRAZOL-5-AMINE'>WVI</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2w7x\|2w7x]], [[2wtc\|2wtc]], [[2wtd\|2wtd]], [[2wti\|2wti]], [[2wtj\|2wtj]], [[2xbj\|2xbj]], [[2xk9\|2xk9]], [[2xm8\|2xm8]], [[2xm9\|2xm9]], [[2ycf\|2ycf]], [[2ycq\|2ycq]], [[2ycr\|2ycr]], [[2ycs\|2ycs]], [[2yiq\|2yiq]], [[2yir\|2yir]], [[2yit\|2yit]], [[4a9r\|4a9r]], [[4a9s\|4a9s]], [[4a9t\|4a9t]], [[4a9u\|4a9u]], [[4bda\|4bda]], [[4bdb\|4bdb]], [[4bdc\|4bdc]], [[4bdd\|4bdd]], [[4bde\|4bde]], [[4bdf\|4bdf]], [[4bdg\|4bdg]], [[4bdi\|4bdi]], [[4bdj\|4bdj]], [[4bdk\|4bdk]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2w7x\|2w7x]], [[2wtc\|2wtc]], [[2wtd\|2wtd]], [[2wti\|2wti]], [[2wtj\|2wtj]], [[2xbj\|2xbj]], [[2xk9\|2xk9]], [[2xm8\|2xm8]], [[2xm9\|2xm9]], [[2ycf\|2ycf]], [[2ycq\|2ycq]], [[2ycr\|2ycr]], [[2ycs\|2ycs]], [[2yiq\|2yiq]], [[2yir\|2yir]], [[2yit\|2yit]], [[4a9r\|4a9r]], [[4a9s\|4a9s]], [[4a9t\|4a9t]], [[4a9u\|4a9u]], [[4bda\|4bda]], [[4bdb\|4bdb]], [[4bdc\|4bdc]], [[4bdd\|4bdd]], [[4bde\|4bde]], [[4bdf\|4bdf]], [[4bdg\|4bdg]], [[4bdi\|4bdi]], [[4bdj\|4bdj]], [[4bdk\|4bdk]]</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~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4bdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bdh OCA], [~~http~~://pdbe.org/4bdh PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4bdh RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4bdh PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4bdh 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=4bdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bdh OCA], [https://pdbe.org/4bdh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bdh RCSB], [https://www.ebi.ac.uk/pdbsum/4bdh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bdh 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 ==
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/>

OCA at 13:11, 13 March 2019

2019-03-13T13:11:23Z

←Older revision		Revision as of 13:11, 13 March 2019
Line 1:		Line 1:

	==Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)==		==Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)==
-	<StructureSection load='4bdh' size='340' side='right' caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>	+	<StructureSection load='4bdh' size='340' side='right'caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BDH FirstGlance]. <br>		<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BDH FirstGlance]. <br>
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: Aherne, G W]]		[[Category: Aherne, G W]]

OCA at 14:21, 11 August 2016

2016-08-11T14:21:24Z

←Older revision		Revision as of 14:21, 11 August 2016
Line 1:		Line 1:
		+
	==Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)==		==Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)==
	<StructureSection load='4bdh' size='340' side='right' caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='4bdh' size='340' side='right' caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BDH FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BDH FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=WVI:3-METHYL-4-(THIOPHEN-2-YL)-1H-PYRAZOL-5-AMINE'>WVI</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=WVI:3-METHYL-4-(THIOPHEN-2-YL)-1H-PYRAZOL-5-AMINE'>WVI</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2w7x\|2w7x]], [[2wtc\|2wtc]], [[2wtd\|2wtd]], [[2wti\|2wti]], [[2wtj\|2wtj]], [[2xbj\|2xbj]], [[2xk9\|2xk9]], [[2xm8\|2xm8]], [[2xm9\|2xm9]], [[2ycf\|2ycf]], [[2ycq\|2ycq]], [[2ycr\|2ycr]], [[2ycs\|2ycs]], [[2yiq\|2yiq]], [[2yir\|2yir]], [[2yit\|2yit]], [[4a9r\|4a9r]], [[4a9s\|4a9s]], [[4a9t\|4a9t]], [[4a9u\|4a9u]], [[4bda\|4bda]], [[4bdb\|4bdb]], [[4bdc\|4bdc]], [[4bdd\|4bdd]], [[4bde\|4bde]], [[4bdf\|4bdf]], [[4bdg\|4bdg]], [[4bdi\|4bdi]], [[4bdj\|4bdj]], [[4bdk\|4bdk]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2w7x\|2w7x]], [[2wtc\|2wtc]], [[2wtd\|2wtd]], [[2wti\|2wti]], [[2wtj\|2wtj]], [[2xbj\|2xbj]], [[2xk9\|2xk9]], [[2xm8\|2xm8]], [[2xm9\|2xm9]], [[2ycf\|2ycf]], [[2ycq\|2ycq]], [[2ycr\|2ycr]], [[2ycs\|2ycs]], [[2yiq\|2yiq]], [[2yir\|2yir]], [[2yit\|2yit]], [[4a9r\|4a9r]], [[4a9s\|4a9s]], [[4a9t\|4a9t]], [[4a9u\|4a9u]], [[4bda\|4bda]], [[4bdb\|4bdb]], [[4bdc\|4bdc]], [[4bdd\|4bdd]], [[4bde\|4bde]], [[4bdf\|4bdf]], [[4bdg\|4bdg]], [[4bdi\|4bdi]], [[4bdj\|4bdj]], [[4bdk\|4bdk]]</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=4bdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bdh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bdh RCSB], [http://www.ebi.ac.uk/pdbsum/4bdh 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=4bdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bdh OCA], [http://pdbe.org/4bdh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bdh RCSB], [http://www.ebi.ac.uk/pdbsum/4bdh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bdh 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 4bdh" 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: Aherne, G W]]		[[Category: Aherne, G W]]

OCA at 07:53, 20 January 2015

2015-01-20T07:53:19Z

←Older revision		Revision as of 07:53, 20 January 2015
Line 1:		Line 1:
-	~~{{STRUCTURE_4bdh\| PDB=4bdh \| SCENE= }}~~	+	==Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)==
-	===Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)===	+	<StructureSection load='4bdh' size='340' side='right' caption='[[4bdh]], [[Resolution\|resolution]] 2.70Å' scene=''>
-	~~{{ABSTRACT_PUBMED_23776527}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4bdh]] 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=4BDH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BDH FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=WVI:3-METHYL-4-(THIOPHEN-2-YL)-1H-PYRAZOL-5-AMINE'>WVI</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1gxc\|1gxc]], [[2cn5\|2cn5]], [[2cn8\|2cn8]], [[2w0j\|2w0j]], [[2w7x\|2w7x]], [[2wtc\|2wtc]], [[2wtd\|2wtd]], [[2wti\|2wti]], [[2wtj\|2wtj]], [[2xbj\|2xbj]], [[2xk9\|2xk9]], [[2xm8\|2xm8]], [[2xm9\|2xm9]], [[2ycf\|2ycf]], [[2ycq\|2ycq]], [[2ycr\|2ycr]], [[2ycs\|2ycs]], [[2yiq\|2yiq]], [[2yir\|2yir]], [[2yit\|2yit]], [[4a9r\|4a9r]], [[4a9s\|4a9s]], [[4a9t\|4a9t]], [[4a9u\|4a9u]], [[4bda\|4bda]], [[4bdb\|4bdb]], [[4bdc\|4bdc]], [[4bdd\|4bdd]], [[4bde\|4bde]], [[4bdf\|4bdf]], [[4bdg\|4bdg]], [[4bdi\|4bdi]], [[4bdj\|4bdj]], [[4bdk\|4bdk]]</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=4bdh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bdh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bdh RCSB], [http://www.ebi.ac.uk/pdbsum/4bdh 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>		[[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 ==
		+	Checkpoint kinase 2 (CHK2) is an important serine/threonine kinase in the cellular response to DNA damage. A fragment-based screening campaign using a combination of a high-concentration AlphaScreen kinase assay and a biophysical thermal shift assay, followed by X-ray crystallography, identified a number of chemically different ligand-efficient CHK2 hinge-binding scaffolds that have not been exploited in known CHK2 inhibitors. In addition, it showed that the use of these orthogonal techniques allowed efficient discrimination between genuine hit matter and false positives from each individual assay technology. Furthermore, the CHK2 crystal structures with a quinoxaline-based fragment and its follow-up compound highlight a hydrophobic area above the hinge region not previously explored in rational CHK2 inhibitor design, but which might be exploited to enhance both potency and selectivity of CHK2 inhibitors.

-	~~==Function==~~	+	Fragment-Based Screening Maps Inhibitor Interactions in the ATP-Binding Site of Checkpoint Kinase 2.,Silva-Santisteban MC, Westwood IM, Boxall K, Brown N, Peacock S, McAndrew C, Barrie E, Richards M, Mirza A, Oliver AW, Burke R, Hoelder S, Jones K, Aherne GW, Blagg J, Collins I, Garrett MD, van Montfort RL PLoS One. 2013 Jun 12;8(6):e65689. doi: 10.1371/journal.pone.0065689. Print 2013. PMID:23776527<ref>PMID:23776527</ref>
-	~~[[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>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4bdh]] 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=4BDH OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:023776527</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
-	[[Category: Aherne, G W.]]	+	[[Category: Aherne, G W]]
-	[[Category: Barrie, E.]]	+	[[Category: Barrie, E]]
-	[[Category: Blagg, J.]]	+	[[Category: Blagg, J]]
-	[[Category: Boxall, K.]]	+	[[Category: Boxall, K]]
-	[[Category: Brown, N.]]	+	[[Category: Brown, N]]
-	[[Category: Burke, R.]]	+	[[Category: Burke, R]]
-	[[Category: Collins, I.]]	+	[[Category: Collins, I]]
-	[[Category: Garrett, M D.]]	+	[[Category: Garrett, M D]]
-	[[Category: Hoelder, S.]]	+	[[Category: Hoelder, S]]
-	[[Category: Jones, K.]]	+	[[Category: Jones, K]]
-	[[Category: McAndrew, C.]]	+	[[Category: McAndrew, C]]
-	[[Category: Mirza, A.]]	+	[[Category: Mirza, A]]
-	[[Category: Montfort, R L.M van.]]	+	[[Category: Montfort, R L.M van]]
-	[[Category: Oliver, A W.]]	+	[[Category: Oliver, A W]]
-	[[Category: Peacock, S.]]	+	[[Category: Peacock, S]]
-	[[Category: Richards, M.]]	+	[[Category: Richards, M]]
-	[[Category: Silva-Santisteban, M C.]]	+	[[Category: Silva-Santisteban, M C]]
-	[[Category: Westwood, I M.]]	+	[[Category: Westwood, I M]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 10:08, 30 June 2013

2013-06-30T10:08:55Z

←Older revision		Revision as of 10:08, 30 June 2013
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	{{STRUCTURE_4bdh\| PDB=4bdh \| SCENE= }}
		+	===Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)===
		+	{{ABSTRACT_PUBMED_23776527}}

-	~~The~~ entry ~~4bdh~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	==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>

-	~~Authors~~: ~~Silva-Santisteban, M~~.C., ~~Westwood, I~~.M., ~~Boxall, K., Brown, N., Peacock,~~ S., ~~McAndrew~~, C.~~, Barrie, E~~.~~, Richards,~~ M., ~~Mirza, A., Oliver, A~~.W., ~~Burke, R~~., ~~Hoelder, S~~.~~, Jones, K~~.~~, Aherne, G.W~~., ~~Blagg, J~~.~~, Collins, I., Garrett, M.D., van Montfort, R.L.M~~.	+	==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>

-	~~Description~~: ~~Fragment~~-~~based screening identifies a new area for inhibitor binding to checkpoint~~ kinase ~~2 (CHK2)~~	+	==About this Structure==
		+	[[4bdh]] 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=4BDH OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:023776527</ref><references group="xtra"/><references/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Aherne, G W.]]
		+	[[Category: Barrie, E.]]
		+	[[Category: Blagg, J.]]
		+	[[Category: Boxall, K.]]
		+	[[Category: Brown, N.]]
		+	[[Category: Burke, R.]]
		+	[[Category: Collins, I.]]
		+	[[Category: Garrett, M D.]]
		+	[[Category: Hoelder, S.]]
		+	[[Category: Jones, K.]]
		+	[[Category: McAndrew, C.]]
		+	[[Category: Mirza, A.]]
		+	[[Category: Montfort, R L.M van.]]
		+	[[Category: Oliver, A W.]]
		+	[[Category: Peacock, S.]]
		+	[[Category: Richards, M.]]
		+	[[Category: Silva-Santisteban, M C.]]
		+	[[Category: Westwood, I M.]]
		+	[[Category: Transferase]]

OCA: Protected "4bdh" [edit=sysop:move=sysop]

2012-10-17T06:24:09Z

Protected "4bdh" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:24, 17 October 2012

OCA: New page: '''Unreleased structure''' The entry 4bdh is ON HOLD until Paper Publication Authors: Silva-Santisteban, M.C., Westwood, I.M., Boxall, K., Brown, N., Peacock, S., McAndrew, C., Barrie, ...

2012-10-17T06:24:08Z

New page: '''Unreleased structure''' The entry 4bdh is ON HOLD until Paper Publication Authors: Silva-Santisteban, M.C., Westwood, I.M., Boxall, K., Brown, N., Peacock, S., McAndrew, C., Barrie, ...

New page

'''Unreleased structure'''

The entry 4bdh is ON HOLD until Paper Publication

Authors: Silva-Santisteban, M.C., Westwood, I.M., Boxall, K., Brown, N., Peacock, S., McAndrew, C., Barrie, E., Richards, M., Mirza, A., Oliver, A.W., Burke, R., Hoelder, S., Jones, K., Aherne, G.W., Blagg, J., Collins, I., Garrett, M.D., van Montfort, R.L.M.

Description: Fragment-based screening identifies a new area for inhibitor binding to checkpoint kinase 2 (CHK2)