4a9r - Revision history

OCA at 11:22, 20 December 2023

OCA — Wed, 20 Dec 2023 11:22:22 GMT

←Older revision		Revision as of 11:22, 20 December 2023
Line 3:		Line 3:
	<StructureSection load='4a9r' size='340' side='right'caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>		<StructureSection load='4a9r' size='340' side='right'caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A9R FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A9R FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=EDO:1,2~~-~~ETHANEDIOL'>EDO</scene>~~, ~~<scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=RU5:2-~~[~~4-(4-CHLOROPHENOXY)PHENYL~~]~~-1H-BENZIMIDAZOLE-6-CARBOXAMIDE'>RU5</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]] 2.85Å</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]], [[2cn8\|2cn8]], [[2ycf\|2ycf]], [[2w0j\|2w0j]], [[2yir\|2yir]], [[2wtc\|2wtc]], [[2yit\|2yit]], [[2ycr\|2ycr]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2wtd\|2wtd]], [[2xbj\|2xbj]], [[2wtj\|2wtj]], [[2ycs\|2ycs]], [[2xk9\|2xk9]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2cn5\|2cn5]], [[2yiq\|2yiq]], [[2xm8\|2xm8]], [[4a9t\|4a9t]], [[4a9s\|4a9s]], [[4a9u\|4a9u]]</~~div~~><~~/td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=RU5:2-[4-(4-CHLOROPHENOXY)PHENYL]-1H-BENZIMIDAZOLE-6-CARBOXAMIDE'>RU5</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=4a9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a9r OCA], [https://pdbe.org/4a9r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a9r RCSB], [https://www.ebi.ac.uk/pdbsum/4a9r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a9r 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=4a9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a9r OCA], [https://pdbe.org/4a9r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a9r RCSB], [https://www.ebi.ac.uk/pdbsum/4a9r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a9r 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 ==
Line 29:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Blagg J]]
-	[[Category: Blagg, J]]	+	[[Category: Choi V]]
-	[[Category: Choi, V]]	+	[[Category: Matijssen C]]
-	[[Category: Matijssen, C]]	+	[[Category: Sheldrake P]]
-	~~[[Category: Montfort, R L.M van~~]]	+	[[Category: Siddique S]]
-	[[Category: Sheldrake, P]]	+	[[Category: Silva-Santisteban MC]]
-	[[Category: Siddique, S]]	+	[[Category: Westwood IM]]
-	[[Category: Silva-Santisteban~~, M C~~]]	+	[[Category: Van Montfort RLM]]
-	[[Category: Westwood~~, I M~~]]	+
-	[[Category: ~~Kinase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:54, 18 August 2022

OCA — Thu, 18 Aug 2022 07:54:30 GMT

←Older revision		Revision as of 07:54, 18 August 2022
Line 3:		Line 3:
	<StructureSection load='4a9r' size='340' side='right'caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>		<StructureSection load='4a9r' size='340' side='right'caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4A9R FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A9R FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=RU5:2-[4-(4-CHLOROPHENOXY)PHENYL]-1H-BENZIMIDAZOLE-6-CARBOXAMIDE'>RU5</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=RU5:2-[4-(4-CHLOROPHENOXY)PHENYL]-1H-BENZIMIDAZOLE-6-CARBOXAMIDE'>RU5</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2cn8\|2cn8]], [[2ycf\|2ycf]], [[2w0j\|2w0j]], [[2yir\|2yir]], [[2wtc\|2wtc]], [[2yit\|2yit]], [[2ycr\|2ycr]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2wtd\|2wtd]], [[2xbj\|2xbj]], [[2wtj\|2wtj]], [[2ycs\|2ycs]], [[2xk9\|2xk9]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2cn5\|2cn5]], [[2yiq\|2yiq]], [[2xm8\|2xm8]], [[4a9t\|4a9t]], [[4a9s\|4a9s]], [[4a9u\|4a9u]]</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]], [[2cn8\|2cn8]], [[2ycf\|2ycf]], [[2w0j\|2w0j]], [[2yir\|2yir]], [[2wtc\|2wtc]], [[2yit\|2yit]], [[2ycr\|2ycr]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2wtd\|2wtd]], [[2xbj\|2xbj]], [[2wtj\|2wtj]], [[2ycs\|2ycs]], [[2xk9\|2xk9]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2cn5\|2cn5]], [[2yiq\|2yiq]], [[2xm8\|2xm8]], [[4a9t\|4a9t]], [[4a9s\|4a9s]], [[4a9u\|4a9u]]</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=4a9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a9r OCA], [~~http~~://pdbe.org/4a9r PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4a9r RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4a9r PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4a9r 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=4a9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a9r OCA], [https://pdbe.org/4a9r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a9r RCSB], [https://www.ebi.ac.uk/pdbsum/4a9r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a9r 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/>
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: Blagg, J]]		[[Category: Blagg, J]]

OCA at 09:29, 6 March 2019

OCA — Wed, 06 Mar 2019 09:29:58 GMT

←Older revision		Revision as of 09:29, 6 March 2019
Line 1:		Line 1:

	==CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR==		==CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR==
-	<StructureSection load='4a9r' size='340' side='right' caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>	+	<StructureSection load='4a9r' size='340' side='right'caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A9R FirstGlance]. <br>		<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A9R FirstGlance]. <br>
Line 34:		Line 34:
	[[Category: Choi, V]]		[[Category: Choi, V]]
	[[Category: Matijssen, C]]		[[Category: Matijssen, C]]
-	[[Category: Montfort, R L.M ~~Van~~]]	+	[[Category: Montfort, R L.M van]]
	[[Category: Sheldrake, P]]		[[Category: Sheldrake, P]]
	[[Category: Siddique, S]]		[[Category: Siddique, S]]

OCA at 15:13, 5 August 2016

OCA — Fri, 05 Aug 2016 15:13:23 GMT

←Older revision		Revision as of 15:13, 5 August 2016
Line 1:		Line 1:
		+
	==CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR==		==CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR==
	<StructureSection load='4a9r' size='340' side='right' caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>		<StructureSection load='4a9r' size='340' side='right' caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A9R FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A9R FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=RU5:2-[4-(4-CHLOROPHENOXY)PHENYL]-1H-BENZIMIDAZOLE-6-CARBOXAMIDE'>RU5</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=RU5:2-[4-(4-CHLOROPHENOXY)PHENYL]-1H-BENZIMIDAZOLE-6-CARBOXAMIDE'>RU5</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2cn8\|2cn8]], [[2ycf\|2ycf]], [[2w0j\|2w0j]], [[2yir\|2yir]], [[2wtc\|2wtc]], [[2yit\|2yit]], [[2ycr\|2ycr]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2wtd\|2wtd]], [[2xbj\|2xbj]], [[2wtj\|2wtj]], [[2ycs\|2ycs]], [[2xk9\|2xk9]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2cn5\|2cn5]], [[2yiq\|2yiq]], [[2xm8\|2xm8]], [[4a9t\|4a9t]], [[4a9s\|4a9s]], [[4a9u\|4a9u]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2cn8\|2cn8]], [[2ycf\|2ycf]], [[2w0j\|2w0j]], [[2yir\|2yir]], [[2wtc\|2wtc]], [[2yit\|2yit]], [[2ycr\|2ycr]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2wtd\|2wtd]], [[2xbj\|2xbj]], [[2wtj\|2wtj]], [[2ycs\|2ycs]], [[2xk9\|2xk9]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2cn5\|2cn5]], [[2yiq\|2yiq]], [[2xm8\|2xm8]], [[4a9t\|4a9t]], [[4a9s\|4a9s]], [[4a9u\|4a9u]]</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=4a9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a9r OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a9r RCSB], [http://www.ebi.ac.uk/pdbsum/4a9r 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=4a9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a9r OCA], [http://pdbe.org/4a9r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4a9r RCSB], [http://www.ebi.ac.uk/pdbsum/4a9r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4a9r 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 4a9r" 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: Blagg, J]]		[[Category: Blagg, J]]

OCA at 09:53, 21 December 2014

OCA — Sun, 21 Dec 2014 09:53:15 GMT

←Older revision		Revision as of 09:53, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4a9r\| PDB=4a9r \| SCENE= }}~~	+	==CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR==
-	===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===	+	<StructureSection load='4a9r' size='340' side='right' caption='[[4a9r]], [[Resolution\|resolution]] 2.85Å' scene=''>
-	~~{{ABSTRACT_PUBMED_23058106}}~~	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4a9r]] 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=4A9R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A9R FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=RU5:2-[4-(4-CHLOROPHENOXY)PHENYL]-1H-BENZIMIDAZOLE-6-CARBOXAMIDE'>RU5</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2wti\|2wti]], [[2cn8\|2cn8]], [[2ycf\|2ycf]], [[2w0j\|2w0j]], [[2yir\|2yir]], [[2wtc\|2wtc]], [[2yit\|2yit]], [[2ycr\|2ycr]], [[2ycq\|2ycq]], [[1gxc\|1gxc]], [[2wtd\|2wtd]], [[2xbj\|2xbj]], [[2wtj\|2wtj]], [[2ycs\|2ycs]], [[2xk9\|2xk9]], [[2xm9\|2xm9]], [[2w7x\|2w7x]], [[2cn5\|2cn5]], [[2yiq\|2yiq]], [[2xm8\|2xm8]], [[4a9t\|4a9t]], [[4a9s\|4a9s]], [[4a9u\|4a9u]]</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=4a9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a9r OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a9r RCSB], [http://www.ebi.ac.uk/pdbsum/4a9r 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 ==
		+	Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature.

-	~~==Disease==~~	+	Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein-ligand crystallography.,Matijssen C, Silva-Santisteban MC, Westwood IM, Siddique S, Choi V, Sheldrake P, van Montfort RL, Blagg J Bioorg Med Chem. 2012 Nov 15;20(22):6630-9. doi: 10.1016/j.bmc.2012.09.024. Epub , 2012 Sep 21. PMID:23058106<ref>PMID:23058106</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==
-	[[~~4a9r]] 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=4A9R OCA~~].	+	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	<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: Blagg, J.]]	+	[[Category: Blagg, J]]
-	[[Category: Choi, V.]]	+	[[Category: Choi, V]]
-	[[Category: Matijssen, C.]]	+	[[Category: Matijssen, C]]
-	[[Category: Montfort, R L.M Van.]]	+	[[Category: Montfort, R L.M Van]]
-	[[Category: Sheldrake, P.]]	+	[[Category: Sheldrake, P]]
-	[[Category: Siddique, S.]]	+	[[Category: Siddique, S]]
-	[[Category: Silva-Santisteban, M C.]]	+	[[Category: Silva-Santisteban, M C]]
-	[[Category: Westwood, I M.]]	+	[[Category: Westwood, I M]]
	[[Category: Kinase]]		[[Category: Kinase]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 00:38, 25 March 2013

OCA — Mon, 25 Mar 2013 00:38:01 GMT

←Older revision		Revision as of 00:38, 25 March 2013
Line 1:		Line 1:
-	[[Image:4a9r.png\|left\|200px]]
-
	{{STRUCTURE_4a9r\| PDB=4a9r \| SCENE= }}		{{STRUCTURE_4a9r\| PDB=4a9r \| SCENE= }}
-
	===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===		===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===
-
	{{ABSTRACT_PUBMED_23058106}}		{{ABSTRACT_PUBMED_23058106}}
		+
		+	==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>

	==About this Structure==		==About this Structure==
	[[4a9r]] 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=4A9R OCA].		[[4a9r]] 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=4A9R OCA].
		+
		+	==Reference==
		+	<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 10:45, 14 November 2012

OCA — Wed, 14 Nov 2012 10:45:34 GMT

←Older revision		Revision as of 10:45, 14 November 2012
Line 5:		Line 5:
	===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===		===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===

		+	{{ABSTRACT_PUBMED_23058106}}

	==About this Structure==		==About this Structure==

OCA at 14:10, 8 November 2012

OCA — Thu, 08 Nov 2012 14:10:45 GMT

←Older revision		Revision as of 14:10, 8 November 2012
Line 5:		Line 5:
	===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===		===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===

-	{{ABSTRACT_PUBMED_23058106}}

	==About this Structure==		==About this Structure==

OCA at 06:47, 24 October 2012

OCA — Wed, 24 Oct 2012 06:47:54 GMT

←Older revision		Revision as of 06:47, 24 October 2012
Line 1:		Line 1:
-	[[Image:4a9r.~~jpg~~\|left\|200px]]	+	[[Image:4a9r.png\|left\|200px]]

	{{STRUCTURE_4a9r\| PDB=4a9r \| SCENE= }}		{{STRUCTURE_4a9r\| PDB=4a9r \| SCENE= }}
Line 5:		Line 5:
	===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===		===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===

		+	{{ABSTRACT_PUBMED_23058106}}

	==About this Structure==		==About this Structure==
-	[[4a9r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A9R OCA].	+	[[4a9r]] 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=4A9R OCA].
		+	[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Blagg, J.]]		[[Category: Blagg, J.]]

OCA at 07:24, 10 October 2012

OCA — Wed, 10 Oct 2012 07:24:16 GMT

←Older revision		Revision as of 07:24, 10 October 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:4a9r.jpg\|left\|200px]]

-	~~The entry~~ 4a9r ~~is ON HOLD~~ ~~until Paper Publication~~	+	{{STRUCTURE_4a9r\| PDB=4a9r \| SCENE= }}

-	~~Authors: Matijssen, C., Silva-Santisteban, M.C., Westwood, I.M., Siddique, S., Choi, V., Sheldrake, P., van Montfort, R.L.M., Blagg, J.~~	+	===CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR===

-	~~Description~~: ~~CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR~~	+
		+	==About this Structure==
		+	[[4a9r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A9R OCA].
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Blagg, J.]]
		+	[[Category: Choi, V.]]
		+	[[Category: Matijssen, C.]]
		+	[[Category: Montfort, R L.M Van.]]
		+	[[Category: Sheldrake, P.]]
		+	[[Category: Siddique, S.]]
		+	[[Category: Silva-Santisteban, M C.]]
		+	[[Category: Westwood, I M.]]
		+	[[Category: Kinase]]
		+	[[Category: Transferase]]