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7s9o

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Binary complex of DNA Polymerase Beta with Ring open Intermediate Fapy-dG in the template position

Structural highlights

7s9o is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.23Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

N6-(2-Deoxy-alpha,beta-d-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamid o pyrimidine (Fapy*dG) is a prevalent form of genomic DNA damage. Fapy*dG is formed in greater amounts under anoxic conditions than the well-studied, chemically related 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodGuo). Fapy*dG is more mutagenic in mammalian cells than 8-oxodGuo. A distinctive property of Fapy*dG is facile epimerization, but prior works with Fapy*dG analogues have precluded determining its effect on chemistry. We present crystallographic characterization of natural Fapy*dG in duplex DNA and as the template base for DNA polymerase beta (Pol beta). Fapy*dG adopts the beta-anomer when base paired with cytosine but exists as a mixture of alpha- and beta-anomers when promutagenically base paired with adenine. Rotation about the bond between the glycosidic nitrogen atom and the pyrimidine ring is also affected by the opposing nucleotide. Sodium cyanoborohydride soaking experiments trap the ring-opened Fapy*dG, demonstrating that ring opening and epimerization occur in the crystalline state. Ring opening and epimerization are facilitated by propitious water molecules that are observed in the structures. Determination of Fapy*dG mutagenicity in wild type and Pol beta knockdown HEK 293T cells indicates that Pol beta contributes to G --> T transversions but also suppresses G --> A transitions. Complementary kinetic studies have determined that Fapy*dG promotes mutagenesis by decreasing the catalytic efficiency of dCMP insertion opposite Fapy*dG, thus reducing polymerase fidelity. Kinetic studies have determined that dCMP incorporation opposite the beta-anomer is approximately 90 times faster than the alpha-anomer. This research identifies the importance of anomer dynamics, a feature unique to formamidopyrimidines, when considering the incorporation of nucleotides opposite Fapy*dG and potentially the repair of this structurally unusual lesion.

Structural Dynamics of a Common Mutagenic Oxidative DNA Lesion in Duplex DNA and during DNA Replication.,Ryan BJ, Yang H, Bacurio JHT, Smith MR, Basu AK, Greenberg MM, Freudenthal BD J Am Chem Soc. 2022 May 11;144(18):8054-8065. doi: 10.1021/jacs.2c00193. Epub, 2022 May 2. PMID:35499923^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bennett RA, Wilson DM 3rd, Wong D, Demple B. Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7166-9. PMID:9207062
↑ Matsumoto Y, Kim K, Katz DS, Feng JA. Catalytic center of DNA polymerase beta for excision of deoxyribose phosphate groups. Biochemistry. 1998 May 5;37(18):6456-64. PMID:9572863 doi:10.1021/bi9727545
↑ DeMott MS, Beyret E, Wong D, Bales BC, Hwang JT, Greenberg MM, Demple B. Covalent trapping of human DNA polymerase beta by the oxidative DNA lesion 2-deoxyribonolactone. J Biol Chem. 2002 Mar 8;277(10):7637-40. Epub 2002 Jan 22. PMID:11805079 doi:10.1074/jbc.C100577200
↑ Parsons JL, Dianova II, Khoronenkova SV, Edelmann MJ, Kessler BM, Dianov GL. USP47 is a deubiquitylating enzyme that regulates base excision repair by controlling steady-state levels of DNA polymerase beta. Mol Cell. 2011 Mar 4;41(5):609-15. doi: 10.1016/j.molcel.2011.02.016. PMID:21362556 doi:10.1016/j.molcel.2011.02.016
↑ Ryan BJ, Yang H, Bacurio JHT, Smith MR, Basu AK, Greenberg MM, Freudenthal BD. Structural Dynamics of a Common Mutagenic Oxidative DNA Lesion in Duplex DNA and during DNA Replication. J Am Chem Soc. 2022 May 11;144(18):8054-8065. doi: 10.1021/jacs.2c00193. Epub, 2022 May 2. PMID:35499923 doi:http://dx.doi.org/10.1021/jacs.2c00193

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7s9o"

Categories: Homo sapiens | Large Structures | Synthetic construct | Freudenthal BD | Ryan BJ

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7s9o]] 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=7S9O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S9O FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 2.23&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=7s9o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s9o OCA], [https://pdbe.org/7s9o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s9o RCSB], [https://www.ebi.ac.uk/pdbsum/7s9o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s9o ProSAT]</span></td></tr>
 </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>
+[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 ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 7s9o" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[DNA polymerase 3D structures|DNA polymerase 3D structures]]
 == References ==
 <references/>

7s9o

From Proteopedia

Current revision

Binary complex of DNA Polymerase Beta with Ring open Intermediate Fapy-dG in the template position

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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Proteopedia Page Contributors and Editors (what is this?)

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