6mr8: Difference between revisions
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==D276G DNA polymerase beta substrate complex with templating adenine and incoming Fapy-dGTP analog== | ==D276G DNA polymerase beta substrate complex with templating adenine and incoming Fapy-dGTP analog== | ||
<StructureSection load='6mr8' size='340' side='right' caption='[[6mr8]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='6mr8' size='340' side='right'caption='[[6mr8]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6mr8]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MR8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MR8 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6mr8]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MR8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MR8 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GKS:1-[2-amino-5-(formylamino)-6-oxo-1,6-dihydropyrimidin-4-yl]-2,5-anhydro-1,3-dideoxy-6-O-[(R)-hydroxy{[(R)-hydroxy(phosphonooxy)phosphoryl]oxy}phosphoryl]-D-ribo-hexitol'>GKS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GKS:1-[2-amino-5-(formylamino)-6-oxo-1,6-dihydropyrimidin-4-yl]-2,5-anhydro-1,3-dideoxy-6-O-[(R)-hydroxy{[(R)-hydroxy(phosphonooxy)phosphoryl]oxy}phosphoryl]-D-ribo-hexitol'>GKS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6dic|6dic]], [[6dia|6dia]], [[6mr7|6mr7]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6dic|6dic]], [[6dia|6dia]], [[6mr7|6mr7]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POLB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6mr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mr8 OCA], [http://pdbe.org/6mr8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mr8 RCSB], [http://www.ebi.ac.uk/pdbsum/6mr8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mr8 ProSAT]</span></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=6mr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mr8 OCA], [http://pdbe.org/6mr8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mr8 RCSB], [http://www.ebi.ac.uk/pdbsum/6mr8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mr8 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Beard, W A]] | [[Category: Beard, W A]] | ||
[[Category: Freudenthal, B D]] | [[Category: Freudenthal, B D]] | ||
Revision as of 10:02, 17 April 2019
D276G DNA polymerase beta substrate complex with templating adenine and incoming Fapy-dGTP analogD276G DNA polymerase beta substrate complex with templating adenine and incoming Fapy-dGTP analog
Structural highlights
Function[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.[1] [2] [3] [4] Publication Abstract from PubMed4,6-Diamino-5-formamidopyrimidine (Fapy*dG) is an abundant form of oxidative DNA damage that is mutagenic and contributes to the pathogenesis of human disease. When Fapy*dG is in its nucleotide triphosphate form, Fapy*dGTP, it is inefficiently cleansed from the nucleotide pool by the responsible enzyme in Escherichia coli MutT and its mammalian homolog MTH1. Therefore, under oxidative stress conditions, Fapy*dGTP could become a pro-mutagenic substrate for insertion into the genome by DNA polymerases. Here, we evaluated insertion kinetics and high-resolution ternary complex crystal structures of a configurationally stable Fapy*dGTP analog, beta-C-Fapy*dGTP, with DNA polymerase beta. The crystallographic snapshots and kinetic data indicate that binding of beta-C-Fapy*dGTP impedes enzyme closure, thus hindering insertion. The structures reveal that an active site residue, Asp276, positions beta-C-Fapy*dGTP so that it distorts the geometry of critical catalytic atoms. Removal of this guardian side chain permits enzyme closure and increases the efficiency of beta-C-Fapy*dG insertion opposite dC. These results highlight the stringent requirements necessary to achieve a closed DNA polymerase active site poised for efficient nucleotide incorporation and illustrate how DNA polymerase beta has evolved to hinder Fapy*dGTP insertion. A guardian residue hinders insertion of a Fapy*dGTP analog by modulating the open-closed DNA polymerase transition.,Smith MR, Shock DD, Beard WA, Greenberg MM, Freudenthal BD, Wilson SH Nucleic Acids Res. 2019 Jan 16. pii: 5289696. doi: 10.1093/nar/gkz002. PMID:30649431[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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