6i8a
From Proteopedia
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==The crystal structure of the Pol2 catalytic domain of DNA polymerase epsilon carrying a P301R substitution.== | ==The crystal structure of the Pol2 catalytic domain of DNA polymerase epsilon carrying a P301R substitution.== | ||
| - | <StructureSection load='6i8a' size='340' side='right' caption='[[6i8a]], [[Resolution|resolution]] 2.65Å' scene=''> | + | <StructureSection load='6i8a' size='340' side='right'caption='[[6i8a]], [[Resolution|resolution]] 2.65Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6i8a]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I8A OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6i8a]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I8A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I8A FirstGlance]. <br> |
| - | </td></tr><tr id=' | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.652Å</td></tr> |
| - | <tr id=' | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</scene>, <scene name='pdbligand=DTP:2-DEOXYADENOSINE+5-TRIPHOSPHATE'>DTP</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene></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=6i8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i8a OCA], [https://pdbe.org/6i8a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i8a RCSB], [https://www.ebi.ac.uk/pdbsum/6i8a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i8a ProSAT]</span></td></tr> | |
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | |
</table> | </table> | ||
== Function == | == Function == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/DPOE_YEAST DPOE_YEAST] DNA polymerase epsilon (DNA polymerase II) participates in chromosomal DNA replication. It is required during synthesis of the leading and lagging DNA strands at the replication fork and binds at/or near replication origins and moves along DNA with the replication fork. It has 3'-5' proofreading exonuclease activity that correct errors arising during DNA replication. It is also involved in DNA synthesis during DNA repair.<ref>PMID:12124389</ref> |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The most frequently recurring cancer-associated DNA polymerase epsilon (Pol epsilon) mutation is a P286R substitution in the exonuclease domain. While originally proposed to increase genome instability by disrupting exonucleolytic proofreading, the P286R variant was later found to be significantly more pathogenic than Pol epsilon proofreading deficiency per se. The mechanisms underlying its stronger impact remained unclear. Here we report the crystal structure of the yeast orthologue, Pol epsilon-P301R, complexed with DNA and an incoming dNTP. Structural changes in the protein are confined to the exonuclease domain, with R301 pointing towards the exonuclease site. Molecular dynamics simulations suggest that R301 interferes with DNA binding to the exonuclease site, an outcome not observed with the exonuclease-inactive Pol epsilon-D290A,E292A variant lacking the catalytic residues. These results reveal a distinct mechanism of exonuclease inactivation by the P301R substitution and a likely basis for its dramatically higher mutagenic and tumorigenic effects. | ||
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| + | Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase epsilon.,Parkash V, Kulkarni Y, Ter Beek J, Shcherbakova PV, Kamerlin SCL, Johansson E Nat Commun. 2019 Jan 22;10(1):373. doi: 10.1038/s41467-018-08114-9. PMID:30670696<ref>PMID:30670696</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6i8a" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[DNA polymerase 3D structures|DNA polymerase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Saccharomyces cerevisiae S288C]] |
| - | [[Category: | + | [[Category: Synthetic construct]] |
| - | [[Category: | + | [[Category: Johansson E]] |
| - | [[Category: | + | [[Category: Parkash V]] |
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Current revision
The crystal structure of the Pol2 catalytic domain of DNA polymerase epsilon carrying a P301R substitution.
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