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5luq

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Revision as of 06:57, 28 March 2018

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Crystal Structure of Human DNA-dependent Protein Kinase Catalytic Subunit (DNA-PKcs)

Structural highlights

5luq is a 4 chain structure with sequence from Human and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Warning: this is a large structure, and loading might take a long time or not happen at all.

Disease

[PRKDC_HUMAN] Severe combined immunodeficiency due to DNA-PKcs deficiency. The disease is caused by mutations affecting the gene represented in this entry.

Function

[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.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a central component of nonhomologous end joining (NHEJ), repairing DNA double-strand breaks that would otherwise lead to apoptosis or cancer. We have solved its structure in complex with the C-terminal peptide of Ku80 at 4.3 angstrom resolution using x-ray crystallography. We show that the 4128-amino acid structure comprises three large structural units: the N-terminal unit, the Circular Cradle, and the Head. Conformational differences between the two molecules in the asymmetric unit are correlated with changes in accessibility of the kinase active site, which are consistent with an allosteric mechanism to bring about kinase activation. The location of KU80ct194 in the vicinity of the breast cancer 1 (BRCA1) binding site suggests competition with BRCA1, leading to pathway selection between NHEJ and homologous recombination.

DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair.,Sibanda BL, Chirgadze DY, Ascher DB, Blundell TL Science. 2017 Feb 3;355(6324):520-524. doi: 10.1126/science.aak9654. Epub 2017, Feb 2. PMID:28154079^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Soubeyrand S, Pope L, Pakuts B, Hache RJ. Threonines 2638/2647 in DNA-PK are essential for cellular resistance to ionizing radiation. Cancer Res. 2003 Mar 15;63(6):1198-201. PMID:12649176
↑ Wechsler T, Chen BP, Harper R, Morotomi-Yano K, Huang BC, Meek K, Cleaver JE, Chen DJ, Wabl M. DNA-PKcs function regulated specifically by protein phosphatase 5. Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1247-52. Epub 2004 Jan 20. PMID:14734805 doi:http://dx.doi.org/10.1073/pnas.0307765100
↑ Ma Y, Lu H, Tippin B, Goodman MF, Shimazaki N, Koiwai O, Hsieh CL, Schwarz K, Lieber MR. A biochemically defined system for mammalian nonhomologous DNA end joining. Mol Cell. 2004 Dec 3;16(5):701-13. PMID:15574326 doi:10.1016/j.molcel.2004.11.017
↑ Yavuzer U, Smith GC, Bliss T, Werner D, Jackson SP. DNA end-independent activation of DNA-PK mediated via association with the DNA-binding protein C1D. Genes Dev. 1998 Jul 15;12(14):2188-99. PMID:9679063
↑ Sibanda BL, Chirgadze DY, Ascher DB, Blundell TL. DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair. Science. 2017 Feb 3;355(6324):520-524. doi: 10.1126/science.aak9654. Epub 2017, Feb 2. PMID:28154079 doi:http://dx.doi.org/10.1126/science.aak9654

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5luq"

@@ Line 3: / Line 3: @@
 <StructureSection load='5luq' size='340' side='right' caption='[[5luq]], [[Resolution|resolution]] 4.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5luq]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LUQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LUQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5luq]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LUQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LUQ FirstGlance]. <br>
 </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=UNK:UNKNOWN'>UNK</scene></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=5luq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5luq OCA], [http://pdbe.org/5luq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5luq RCSB], [http://www.ebi.ac.uk/pdbsum/5luq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5luq ProSAT]</span></td></tr>
@@ Line 26: / Line 26: @@
 </StructureSection>
 [[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Ascher, D B]]
 [[Category: Blundell, T L]]

5luq

From Proteopedia

Revision as of 06:57, 28 March 2018

Crystal Structure of Human DNA-dependent Protein Kinase Catalytic Subunit (DNA-PKcs)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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