OCA at 07:13, 2 February 2022

2022-02-02T07:13:42Z

←Older revision		Revision as of 07:13, 2 February 2022
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	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
-	[[Category: Blundell, T L.B]]	+	[[Category: Blundell, T L]]
-	[[Category: Liang, S L]]	+	[[Category: Liang, S]]
-	[[Category: Thomas, S E.T]]	+	[[Category: Thomas, S E]]
	[[Category: Complex]]		[[Category: Complex]]
	[[Category: Dna binding protein]]		[[Category: Dna binding protein]]
	[[Category: Dna repair]]		[[Category: Dna repair]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]

OCA at 07:40, 19 January 2022

2022-01-19T07:40:01Z

←Older revision		Revision as of 07:40, 19 January 2022
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	==Cryo-EM structure of DNA-PKcs in complex with NU7441==		==Cryo-EM structure of DNA-PKcs in complex with NU7441==
-	<StructureSection load='7otm' size='340' side='right'caption='[[7otm]]' scene=''>	+	<StructureSection load='7otm' size='340' side='right'caption='[[7otm]], [[Resolution\|resolution]] 3.33Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OTM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OTM FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7otm]] 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=7OTM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OTM FirstGlance]. <br>
-	</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=7otm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7otm OCA], [https://pdbe.org/7otm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7otm RCSB], [https://www.ebi.ac.uk/pdbsum/7otm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7otm ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2R4:8-(DIBENZO[B,D]THIOPHEN-4-YL)-2-(MORPHOLIN-4-YL)-4H-CHROMEN-4-ONE'>2R4</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=UNK:UNKNOWN'>UNK</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=7otm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7otm OCA], [https://pdbe.org/7otm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7otm RCSB], [https://www.ebi.ac.uk/pdbsum/7otm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7otm ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[https://www.uniprot.org/uniprot/PRKDC_HUMAN PRKDC_HUMAN]] Severe combined immunodeficiency due to DNA-PKcs deficiency. The disease is caused by mutations affecting the gene represented in this entry.
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/PRKDC_HUMAN PRKDC_HUMAN]] Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break (DSB) repair and V(D)J recombination. Must be bound to DNA to express its catalytic properties. Promotes processing of hairpin DNA structures in V(D)J recombination by activation of the hairpin endonuclease artemis (DCLRE1C). The assembly of the DNA-PK complex at DNA ends is also required for the NHEJ ligation step. Required to protect and align broken ends of DNA. May also act as a scaffold protein to aid the localization of DNA repair proteins to the site of damage. Found at the ends of chromosomes, suggesting a further role in the maintenance of telomeric stability and the prevention of chromosomal end fusion. Also involved in modulation of transcription. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX, thereby regulating DNA damage response mechanism. Phosphorylates DCLRE1C, c-Abl/ABL1, histone H1, HSPCA, c-jun/JUN, p53/TP53, PARP1, POU2F1, DHX9, SRF, XRCC1, XRCC1, XRCC4, XRCC5, XRCC6, WRN, MYC and RFA2. Can phosphorylate C1D not only in the presence of linear DNA but also in the presence of supercoiled DNA. Ability to phosphorylate p53/TP53 in the presence of supercoiled DNA is dependent on C1D. Contributes to the determination of the circadian period length by antagonizing phosphorylation of CRY1 'Ser-588' and increasing CRY1 protein stability, most likely through an indirect machanism. Interacts with CRY1 and CRY2; negatively regulates CRY1 phosphorylation.<ref>PMID:12649176</ref> <ref>PMID:14734805</ref> <ref>PMID:15574326</ref> <ref>PMID:9679063</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has a central role in non-homologous end joining, one of the two main pathways that detect and repair DNA double-strand breaks (DSBs) in humans(1,2). DNA-PKcs is of great importance in repairing pathological DSBs, making DNA-PKcs inhibitors attractive therapeutic agents for cancer in combination with DSB-inducing radiotherapy and chemotherapy(3). Many of the selective inhibitors of DNA-PKcs that have been developed exhibit potential as treatment for various cancers(4). Here we report cryo-electron microscopy (cryo-EM) structures of human DNA-PKcs natively purified from HeLa cell nuclear extracts, in complex with adenosine-5'-(gamma-thio)-triphosphate (ATPgammaS) and four inhibitors (wortmannin, NU7441, AZD7648 and M3814), including drug candidates undergoing clinical trials. The structures reveal molecular details of ATP binding at the active site before catalysis and provide insights into the modes of action and specificities of the competitive inhibitors. Of note, binding of the ligands causes movement of the PIKK regulatory domain (PRD), revealing a connection between the p-loop and PRD conformations. Electrophoretic mobility shift assay and cryo-EM studies on the DNA-dependent protein kinase holoenzyme further show that ligand binding does not have a negative allosteric or inhibitory effect on assembly of the holoenzyme complex and that inhibitors function through direct competition with ATP. Overall, the structures described in this study should greatly assist future efforts in rational drug design targeting DNA-PKcs, demonstrating the potential of cryo-EM in structure-guided drug development for large and challenging targets.
		+
		+	Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs.,Liang S, Thomas SE, Chaplin AK, Hardwick SW, Chirgadze DY, Blundell TL Nature. 2022 Jan 5. pii: 10.1038/s41586-021-04274-9. doi:, 10.1038/s41586-021-04274-9. PMID:34987222<ref>PMID:34987222</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7otm" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Blundell ~~TLB~~]]	+	[[Category: Non-specific serine/threonine protein kinase]]
-	[[Category: Liang SL]]	+	[[Category: Blundell, T L.B]]
-	[[Category: Thomas ~~SET~~]]	+	[[Category: Liang, S L]]
		+	[[Category: Thomas, S E.T]]
		+	[[Category: Complex]]
		+	[[Category: Dna binding protein]]
		+	[[Category: Dna repair]]
		+	[[Category: Inhibitor]]

OCA at 09:57, 12 January 2022

2022-01-12T09:57:52Z

←Older revision		Revision as of 09:57, 12 January 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 7otm is ~~ON HOLD until Paper Publication~~	+	==Cryo-EM structure of DNA-PKcs in complex with NU7441==
-		+	<StructureSection load='7otm' size='340' side='right'caption='[[7otm]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OTM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OTM FirstGlance]. <br>
-	~~Description~~:	+	</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=7otm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7otm OCA], [https://pdbe.org/7otm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7otm RCSB], [https://www.ebi.ac.uk/pdbsum/7otm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7otm ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Blundell TLB]]
		+	[[Category: Liang SL]]
		+	[[Category: Thomas SET]]

OCA at 06:20, 25 June 2021

2021-06-25T06:20:49Z

←Older revision		Revision as of 06:20, 25 June 2021
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7otm is ON HOLD	+	The entry 7otm is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7otm" [edit=sysop:move=sysop]

2021-06-17T13:53:48Z

Protected "7otm" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:53, 17 June 2021

OCA: New page: '''Unreleased structure''' The entry 7otm is ON HOLD Authors: Description: Category: Unreleased Structures

2021-06-17T13:53:47Z

New page: '''Unreleased structure''' The entry 7otm is ON HOLD Authors: Description: Category: Unreleased Structures

New page