6brx

From Proteopedia

(Difference between revisions)

Revision as of 08:36, 8 January 2020

Crystal Structure of Human DNA polymerase kappa in complex with DNA containing the major cisplatin lesion

Structural highlights

6brx is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Gene:	POLK, DINB1 (HUMAN)
Activity:	DNA-directed DNA polymerase, with EC number 2.7.7.7
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Cisplatin (cis-diamminedichloroplatinum) is a common chemotherapeutic drug that reacts with the N7 atoms of adjacent guanines in DNA to form the Pt-1,2-d(GpG) intrastrand cross-link (Pt-GG), a major product to block DNA replication. Translesion DNA synthesis has been implicated in chemoresistance during cisplatin treatment of cancer due to Pt-GG lesion bypass. Gene knockdown studies in human cells have indicated a role for polkappa during translesion synthesis of the Pt-GG lesion. However, the bypass activity of polkappa with cisplatin lesions has not been well characterized. In this study, we investigated polkappa's ability to bypass Pt-GG lesion in vitro and determined two crystal structures of polkappa in complex with Pt-GG DNA. The ternary complex structures represent two consecutive stages of lesion bypass: nucleotide insertion opposite the 5'G (Pt-GG2) and primer extension immediately after the lesion (Pt-GG3). Our biochemical data showed that polkappa is very efficient and accurate in extending DNA primers after the first G of the Pt-GG lesion. The structures demonstrate that the efficiency and accuracy is achieved by stably accommodating the bases with the cisplatin adduct in the active site for proper Watson-Crick base pairing with the incoming nucleotide in both the second insertion and post-insertion complexes. Our studies suggest that polkappa works as an extender for efficient replication of the Pt-GG lesion in cells. This work holds promise for considering polkappa, along with poleta, as potential targets for drug design, which together could improve the efficacy of cisplatin treatment for cancer therapy.

Structural Basis for Human DNA Polymerase Kappa to Bypass Cisplatin Intrastrand Cross-Link (Pt-GG) Lesion as an Efficient and Accurate Extender.,Jha V, Ling H J Mol Biol. 2018 May 25;430(11):1577-1589. doi: 10.1016/j.jmb.2018.04.023. Epub, 2018 Apr 30. PMID:29715472^[8]

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

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
↑ Jha V, Ling H. Structural Basis for Human DNA Polymerase Kappa to Bypass Cisplatin Intrastrand Cross-Link (Pt-GG) Lesion as an Efficient and Accurate Extender. J Mol Biol. 2018 May 25;430(11):1577-1589. doi: 10.1016/j.jmb.2018.04.023. Epub, 2018 Apr 30. PMID:29715472 doi:http://dx.doi.org/10.1016/j.jmb.2018.04.023

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/6brx"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Human DNA polymerase kappa in complex with DNA containing the major cisplatin lesion==
-<StructureSection load='6brx' size='340' side='right' caption='[[6brx]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<StructureSection load='6brx' size='340' side='right'caption='[[6brx]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6brx]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BRX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BRX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6brx]] is a 6 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=6BRX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BRX FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0KX:2-DEOXY-5-O-[(R)-HYDROXY{[(R)-HYDROXY(PHOSPHONOOXY)PHOSPHORYL]AMINO}PHOSPHORYL]CYTIDINE'>0KX</scene>, <scene name='pdbligand=CPT:CISPLATIN'>CPT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POLK, DINB1 ([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=6brx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6brx OCA], [http://pdbe.org/6brx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6brx RCSB], [http://www.ebi.ac.uk/pdbsum/6brx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6brx ProSAT]</span></td></tr>
@@ Line 19: / Line 20: @@
 </div>
 <div class="pdbe-citations 6brx" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[DNA polymerase 3D structures|DNA polymerase 3D structures]]
 == References ==
 <references/>
@@ Line 24: / Line 28: @@
 </StructureSection>
 [[Category: DNA-directed DNA polymerase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Jha, V K]]
 [[Category: Ling, H]]

6brx

From Proteopedia

Revision as of 08:36, 8 January 2020

Crystal Structure of Human DNA polymerase kappa in complex with DNA containing the major cisplatin lesion

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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