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==DNA Polymerase Mu, 8-oxodGTP:Ct Reaction State Ternary Complex, 10 mM Mn2+ (40min)== | ==DNA Polymerase Mu, 8-oxodGTP:Ct Reaction State Ternary Complex, 10 mM Mn2+ (40min)== | ||
<StructureSection load='7ktb' size='340' side='right'caption='[[7ktb]]' scene=''> | <StructureSection load='7ktb' size='340' side='right'caption='[[7ktb]], [[Resolution|resolution]] 1.58Å' 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=7KTB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KTB FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ktb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] 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=7KTB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KTB 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=7ktb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ktb OCA], [https://pdbe.org/7ktb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ktb RCSB], [https://www.ebi.ac.uk/pdbsum/7ktb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ktb ProSAT]</span></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]] 1.576Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8DG:8-OXO-2-DEOXYGUANOSINE-5-TRIPHOSPHATE'>8DG</scene>, <scene name='pdbligand=8OG:8-OXO-2-DEOXY-GUANOSINE-5-MONOPHOSPHATE'>8OG</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PPV:PYROPHOSPHATE'>PPV</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=7ktb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ktb OCA], [https://pdbe.org/7ktb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ktb RCSB], [https://www.ebi.ac.uk/pdbsum/7ktb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ktb ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/DPOLM_HUMAN DPOLM_HUMAN] Gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ). Participates in immunoglobulin (Ig) light chain gene rearrangement in V(D)J recombination.<ref>PMID:12640116</ref> <ref>PMID:12888504</ref> <ref>PMID:17483519</ref> <ref>PMID:17915942</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Oxidized dGTP (8-oxo-7,8-dihydro-2 -deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase mu undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine (A(t)). Rotation of A(t) into the syn-conformation enabled undamaged dGTP misinsertion. Exploiting metal and substrate dynamics in a rigid active site allows 8-oxodGTP to circumvent polymerase fidelity safeguards to promote pro-mutagenic double strand break repair. | |||
Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide.,Jamsen JA, Sassa A, Shock DD, Beard WA, Wilson SH Nat Commun. 2021 Apr 6;12(1):2059. doi: 10.1038/s41467-021-21354-6. PMID:33824325<ref>PMID:33824325</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ktb" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[DNA polymerase 3D structures|DNA polymerase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Synthetic construct]] | |||
[[Category: Jamsen JA]] | [[Category: Jamsen JA]] | ||
[[Category: Wilson SH]] | [[Category: Wilson SH]] | ||
Latest revision as of 14:32, 30 October 2024
DNA Polymerase Mu, 8-oxodGTP:Ct Reaction State Ternary Complex, 10 mM Mn2+ (40min)DNA Polymerase Mu, 8-oxodGTP:Ct Reaction State Ternary Complex, 10 mM Mn2+ (40min)
Structural highlights
FunctionDPOLM_HUMAN Gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ). Participates in immunoglobulin (Ig) light chain gene rearrangement in V(D)J recombination.[1] [2] [3] [4] Publication Abstract from PubMedOxidized dGTP (8-oxo-7,8-dihydro-2 -deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase mu undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine (A(t)). Rotation of A(t) into the syn-conformation enabled undamaged dGTP misinsertion. Exploiting metal and substrate dynamics in a rigid active site allows 8-oxodGTP to circumvent polymerase fidelity safeguards to promote pro-mutagenic double strand break repair. Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide.,Jamsen JA, Sassa A, Shock DD, Beard WA, Wilson SH Nat Commun. 2021 Apr 6;12(1):2059. doi: 10.1038/s41467-021-21354-6. PMID:33824325[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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