6u6b
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| - | ==== | + | ==Structure of human DNA polymerase beta misinserting dAMPNPP opposite the 5'G of the cisplatin Pt-GG intrastrand crosslink with Manganese in the active site== |
| - | <StructureSection load='6u6b' size='340' side='right'caption='[[6u6b]]' scene=''> | + | <StructureSection load='6u6b' size='340' side='right'caption='[[6u6b]], [[Resolution|resolution]] 3.11Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6u6b]] is a 4 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=6U6B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U6B FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.108Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CPT:CISPLATIN'>CPT</scene>, <scene name='pdbligand=DZ4:2-DEOXY-5-O-[(R)-HYDROXY{[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]AMINO}PHOSPHORYL]ADENOSINE'>DZ4</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=6u6b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u6b OCA], [https://pdbe.org/6u6b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u6b RCSB], [https://www.ebi.ac.uk/pdbsum/6u6b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u6b ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/DPOLB_HUMAN DPOLB_HUMAN] Repair polymerase that plays a key role in base-excision repair. Has 5'-deoxyribose-5-phosphate lyase (dRP lyase) activity that removes the 5' sugar phosphate and also acts as a DNA polymerase that adds one nucleotide to the 3' end of the arising single-nucleotide gap. Conducts 'gap-filling' DNA synthesis in a stepwise distributive fashion rather than in a processive fashion as for other DNA polymerases.<ref>PMID:9207062</ref> <ref>PMID:9572863</ref> <ref>PMID:11805079</ref> <ref>PMID:21362556</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The cisplatin-1,2-d(GpG) (Pt-GG) intrastrand cross-link is the predominant DNA lesion generated by cisplatin. Cisplatin has been shown to predominantly induce G to T mutations and Pt-GG permits significant misincorporation of dATP by human DNA polymerase beta (polbeta). In agreement, polbeta overexpression, which is frequently observed in cancer cells, is linked to cisplatin resistance and a mutator phenotype. However, the structural basis for the misincorporation of dATP opposite Pt-GG is unknown. Here, we report the first structures of a DNA polymerase inaccurately bypassing Pt-GG. We solved two structures of polbeta misincorporating dATP opposite the 5'-dG of Pt-GG in the presence of Mg2+ or Mn2+. The Mg2+-bound structure exhibits a sub-optimal conformation for catalysis, while the Mn2+-bound structure is in a catalytically more favorable semi-closed conformation. In both structures, dATP does not form a coplanar base pairing with Pt-GG. In the polbeta active site, the syn-dATP opposite Pt-GG appears to be stabilized by protein templating and pi stacking interactions, which resembles the polbeta-mediated dATP incorporation opposite an abasic site. Overall, our results suggest that the templating Pt-GG in the polbeta active site behaves like an abasic site, promoting the insertion of dATP in a non-instructional manner. | ||
| + | |||
| + | Structural insights into the promutagenic bypass of the major cisplatin-induced DNA lesion.,Ouzon-Shubeita H, Vilas CK, Lee S Biochem J. 2020 Mar 13;477(5):937-951. doi: 10.1042/BCJ20190906. PMID:32039434<ref>PMID:32039434</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6u6b" 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: | + | [[Category: Lee S]] |
| + | [[Category: Ouzon-Shubeita H]] | ||
| + | [[Category: Vilas CK]] | ||
Current revision
Structure of human DNA polymerase beta misinserting dAMPNPP opposite the 5'G of the cisplatin Pt-GG intrastrand crosslink with Manganese in the active site
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