7r3y: Difference between revisions
New page: '''Unreleased structure''' The entry 7r3y is ON HOLD Authors: Barbari, S.R., Beach, A.K., Markgren, J.G., Parkash, V., Johansson, E., Shcherbakova, P.V. Description: The crystal struct... |
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The | ==The crystal structure of the V426L variant of Pol2CORE in complex with DNA and an incoming nucleotide== | ||
<StructureSection load='7r3y' size='340' side='right'caption='[[7r3y]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7r3y]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] 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=7R3Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7R3Y FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> | |||
<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></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=7r3y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7r3y OCA], [https://pdbe.org/7r3y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7r3y RCSB], [https://www.ebi.ac.uk/pdbsum/7r3y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7r3y ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Amino acid substitutions in the exonuclease domain of DNA polymerase (Pol) cause ultramutated tumors. Studies in model organisms suggested pathogenic mechanisms distinct from a simple loss of exonuclease. These mechanisms remain unclear for most recurrent Pol mutations. Particularly, the highly prevalent V411L variant remained a long-standing puzzle with no detectable mutator effect in yeast despite the unequivocal association with ultramutation in cancers. Using purified four-subunit yeast Pol, we assessed the consequences of substitutions mimicking human V411L, S459F, F367S, L424V and D275V. While the effects on exonuclease activity vary widely, all common cancer-associated variants have increased DNA polymerase activity. Notably, the analog of Pol-V411L is among the strongest polymerases, and structural analysis suggests defective polymerase-to-exonuclease site switching. We further show that the V411L analog produces a robust mutator phenotype in strains that lack mismatch repair, indicating a high rate of replication errors. Lastly, unlike wild-type and exonuclease-dead Pol, hyperactive variants efficiently synthesize DNA at low dNTP concentrations. We propose that this characteristic could promote cancer cell survival and preferential participation of mutator polymerases in replication during metabolic stress. Our results support the notion that polymerase fitness, rather than low fidelity alone, is an important determinant of variant pathogenicity. | |||
Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase variants at low dNTP levels.,Barbari SR, Beach AK, Markgren JG, Parkash V, Moore EA, Johansson E, Shcherbakova PV Nucleic Acids Res. 2022 Aug 12;50(14):8023-8040. doi: 10.1093/nar/gkac602. PMID:35822874<ref>PMID:35822874</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7r3y" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Johansson | ==See Also== | ||
[[Category: Markgren | *[[DNA polymerase 3D structures|DNA polymerase 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Saccharomyces cerevisiae]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Barbari SR]] | |||
[[Category: Beach AK]] | |||
[[Category: Johansson E]] | |||
[[Category: Markgren JG]] | |||
[[Category: Parkash V]] | |||
[[Category: Shcherbakova PV]] | |||
Latest revision as of 16:25, 1 February 2024
The crystal structure of the V426L variant of Pol2CORE in complex with DNA and an incoming nucleotideThe crystal structure of the V426L variant of Pol2CORE in complex with DNA and an incoming nucleotide
Structural highlights
Publication Abstract from PubMedAmino acid substitutions in the exonuclease domain of DNA polymerase (Pol) cause ultramutated tumors. Studies in model organisms suggested pathogenic mechanisms distinct from a simple loss of exonuclease. These mechanisms remain unclear for most recurrent Pol mutations. Particularly, the highly prevalent V411L variant remained a long-standing puzzle with no detectable mutator effect in yeast despite the unequivocal association with ultramutation in cancers. Using purified four-subunit yeast Pol, we assessed the consequences of substitutions mimicking human V411L, S459F, F367S, L424V and D275V. While the effects on exonuclease activity vary widely, all common cancer-associated variants have increased DNA polymerase activity. Notably, the analog of Pol-V411L is among the strongest polymerases, and structural analysis suggests defective polymerase-to-exonuclease site switching. We further show that the V411L analog produces a robust mutator phenotype in strains that lack mismatch repair, indicating a high rate of replication errors. Lastly, unlike wild-type and exonuclease-dead Pol, hyperactive variants efficiently synthesize DNA at low dNTP concentrations. We propose that this characteristic could promote cancer cell survival and preferential participation of mutator polymerases in replication during metabolic stress. Our results support the notion that polymerase fitness, rather than low fidelity alone, is an important determinant of variant pathogenicity. Enhanced polymerase activity permits efficient synthesis by cancer-associated DNA polymerase variants at low dNTP levels.,Barbari SR, Beach AK, Markgren JG, Parkash V, Moore EA, Johansson E, Shcherbakova PV Nucleic Acids Res. 2022 Aug 12;50(14):8023-8040. doi: 10.1093/nar/gkac602. PMID:35822874[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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