|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Structure of human DNA polymerase kappa inserting dATP opposite an 8-oxoG DNA lesion== | | ==Structure of human DNA polymerase kappa inserting dATP opposite an 8-oxoG DNA lesion== |
| - | <StructureSection load='3in5' size='340' side='right' caption='[[3in5]], [[Resolution|resolution]] 3.20Å' scene=''> | + | <StructureSection load='3in5' size='340' side='right'caption='[[3in5]], [[Resolution|resolution]] 3.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3in5]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3hed 3hed]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IN5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3IN5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3in5]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3hed 3hed]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IN5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3IN5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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]] 3.2Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=8OG:8-OXO-2-DEOXY-GUANOSINE-5-MONOPHOSPHATE'>8OG</scene>, <scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8OG:8-OXO-2-DEOXY-GUANOSINE-5-MONOPHOSPHATE'>8OG</scene>, <scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1t94|1t94]], [[2oh2|2oh2]]</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=3in5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3in5 OCA], [https://pdbe.org/3in5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3in5 RCSB], [https://www.ebi.ac.uk/pdbsum/3in5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3in5 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DINB1, POLK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] </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=3in5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3in5 OCA], [http://pdbe.org/3in5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3in5 RCSB], [http://www.ebi.ac.uk/pdbsum/3in5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3in5 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/POLK_HUMAN POLK_HUMAN]] DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity.<ref>PMID:10620008</ref> <ref>PMID:11024016</ref> <ref>PMID:12145297</ref> <ref>PMID:12444249</ref> <ref>PMID:12952891</ref> <ref>PMID:14630940</ref> <ref>PMID:15533436</ref> | + | [https://www.uniprot.org/uniprot/POLK_HUMAN POLK_HUMAN] DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity.<ref>PMID:10620008</ref> <ref>PMID:11024016</ref> <ref>PMID:12145297</ref> <ref>PMID:12444249</ref> <ref>PMID:12952891</ref> <ref>PMID:14630940</ref> <ref>PMID:15533436</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 34: |
Line 31: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[DNA polymerase|DNA polymerase]] | + | *[[DNA polymerase 3D structures|DNA polymerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: DNA-directed DNA polymerase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Aggarwal, A K]] | + | [[Category: Aggarwal AK]] |
| - | [[Category: Carpio, R Vasquez-Del]]
| + | [[Category: Silverstein TD]] |
| - | [[Category: Silverstein, T D]] | + | [[Category: Vasquez-Del Carpio R]] |
| - | [[Category: Alternative splicing]] | + | |
| - | [[Category: Dna damage]]
| + | |
| - | [[Category: Dna repair]]
| + | |
| - | [[Category: Dna replication]]
| + | |
| - | [[Category: Dna synthesis]]
| + | |
| - | [[Category: Dna-binding]]
| + | |
| - | [[Category: Dna-directed dna polymerase]]
| + | |
| - | [[Category: Magnesium]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Mutator protein]]
| + | |
| - | [[Category: Nucleotidyltransferase]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Schiff base]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-dna complex]]
| + | |
| - | [[Category: Zinc]]
| + | |
| - | [[Category: Zinc-finger]]
| + | |
| Structural highlights
Function
POLK_HUMAN DNA polymerase specifically involved in DNA repair. Plays an important role in translesion synthesis, where the normal high-fidelity DNA polymerases cannot proceed and DNA synthesis stalls. Depending on the context, it inserts the correct base, but causes frequent base transitions, transversions and frameshifts. Lacks 3'-5' proofreading exonuclease activity. Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have lyase activity.[1] [2] [3] [4] [5] [6] [7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: Oxygen-free radicals formed during normal aerobic cellular metabolism attack bases in DNA and 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the major lesions formed. It is amongst the most mutagenic lesions in cells because of its dual coding potential, wherein 8-oxoG(syn) can pair with an A in addition to normal base pairing of 8-oxoG(anti) with a C. Human DNA polymerase kappa (Polkappa) is a member of the newly discovered Y-family of DNA polymerases that possess the ability to replicate through DNA lesions. To understand the basis of Polkappa's preference for insertion of an A opposite 8-oxoG lesion, we have solved the structure of Polkappa in ternary complex with a template-primer presenting 8-oxoG in the active site and with dATP as the incoming nucleotide. METHODOLOGY AND PRINCIPAL FINDINGS: We show that the Polkappa active site is well-adapted to accommodate 8-oxoG in the syn conformation. That is, the polymerase and the bound template-primer are almost identical in their conformations to that in the ternary complex with undamaged DNA. There is no steric hindrance to accommodating 8-oxoG in the syn conformation for Hoogsteen base-paring with incoming dATP. CONCLUSIONS AND SIGNIFICANCE: The structure we present here is the first for a eukaryotic translesion synthesis (TLS) DNA polymerase with an 8-oxoG:A base pair in the active site. The structure shows why Polkappa is more efficient at inserting an A opposite the 8-oxoG lesion than a C. The structure also provides a basis for why Polkappa is more efficient at inserting an A opposite the lesion than other Y-family DNA polymerases.
Structure of human DNA polymerase kappa inserting dATP opposite an 8-OxoG DNA lesion.,Vasquez-Del Carpio R, Silverstein TD, Lone S, Swan MK, Choudhury JR, Johnson RE, Prakash S, Prakash L, Aggarwal AK PLoS One. 2009 Jun 2;4(6):e5766. PMID:19492058[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ogi T, Kato T Jr, Kato T, Ohmori H. Mutation enhancement by DINB1, a mammalian homologue of the Escherichia coli mutagenesis protein dinB. Genes Cells. 1999 Nov;4(11):607-18. PMID:10620008
- ↑ Gerlach VL, Feaver WJ, Fischhaber PL, Friedberg EC. Purification and characterization of pol kappa, a DNA polymerase encoded by the human DINB1 gene. J Biol Chem. 2001 Jan 5;276(1):92-8. PMID:11024016 doi:http://dx.doi.org/10.1074/jbc.M004413200
- ↑ Fischhaber PL, Gerlach VL, Feaver WJ, Hatahet Z, Wallace SS, Friedberg EC. Human DNA polymerase kappa bypasses and extends beyond thymine glycols during translesion synthesis in vitro, preferentially incorporating correct nucleotides. J Biol Chem. 2002 Oct 4;277(40):37604-11. Epub 2002 Jul 26. PMID:12145297 doi:10.1074/jbc.M206027200
- ↑ Haracska L, Prakash L, Prakash S. Role of human DNA polymerase kappa as an extender in translesion synthesis. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16000-5. Epub 2002 Nov 20. PMID:12444249 doi:10.1073/pnas.252524999
- ↑ Wolfle WT, Washington MT, Prakash L, Prakash S. Human DNA polymerase kappa uses template-primer misalignment as a novel means for extending mispaired termini and for generating single-base deletions. Genes Dev. 2003 Sep 1;17(17):2191-9. PMID:12952891 doi:http://dx.doi.org/10.1101/gad.1108603
- ↑ Haracska L, Prakash L, Prakash S. A mechanism for the exclusion of low-fidelity human Y-family DNA polymerases from base excision repair. Genes Dev. 2003 Nov 15;17(22):2777-85. PMID:14630940 doi:10.1101/gad.1146103
- ↑ Yasui M, Suzuki N, Miller H, Matsuda T, Matsui S, Shibutani S. Translesion synthesis past 2'-deoxyxanthosine, a nitric oxide-derived DNA adduct, by mammalian DNA polymerases. J Mol Biol. 2004 Nov 26;344(3):665-74. PMID:15533436 doi:S0022-2836(04)01222-7
- ↑ Vasquez-Del Carpio R, Silverstein TD, Lone S, Swan MK, Choudhury JR, Johnson RE, Prakash S, Prakash L, Aggarwal AK. Structure of human DNA polymerase kappa inserting dATP opposite an 8-OxoG DNA lesion. PLoS One. 2009 Jun 2;4(6):e5766. PMID:19492058 doi:10.1371/journal.pone.0005766
|
