6nkr

From Proteopedia

(Difference between revisions)

Revision as of 11:21, 22 July 2020

Ternary complex crystal structure of K289M variant of DNA polymerase Beta with dGTP

Structural highlights

6nkr is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
NonStd Res:
Gene:	POLB (HUMAN)
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

The human DNA polymerase (pol) beta cancer variant K289M has altered polymerase activity in vitro, and the structure of wild-type pol beta reveals that the K289 side chain contributes to a network of stabilizing interactions in a C-terminal region of the enzyme distal to the active site. Here, we probed the capacity of the K289M variant to tolerate strain introduced within the C-terminal region and active site. Strain was imposed by making use of a dGTP analogue containing a CF2 group substitution for the beta-gamma bridging oxygen atom. The ternary complex structure of the K289M variant displays an alteration in the C-terminal region, whereas the structure of wild-type pol beta is not altered in the presence of the dGTP CF2 analogue. The alteration in the K289M variant impacts the active site, because the enzyme in the ternary complex fails to adopt the normal open to closed conformational change and assembly of the catalytically competent active site. These results reveal the importance of the K289-mediated stabilizing network in the C-terminal region of pol beta and suggest an explanation for why the K289M cancer variant is deficient in polymerase activity even though the position 289 side chain is distal to the active site.

Revealing an Internal Stabilization Deficiency in the DNA Polymerase beta K289M Cancer Variant through the Combined Use of Chemical Biology and X-ray Crystallography.,Batra VK, Alnajjar KS, Sweasy JB, McKenna CE, Goodman MF, Wilson SH Biochemistry. 2020 Mar 3;59(8):955-963. doi: 10.1021/acs.biochem.9b01072. Epub, 2020 Feb 12. PMID:31999437^[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
↑ Batra VK, Alnajjar KS, Sweasy JB, McKenna CE, Goodman MF, Wilson SH. Revealing an Internal Stabilization Deficiency in the DNA Polymerase beta K289M Cancer Variant through the Combined Use of Chemical Biology and X-ray Crystallography. Biochemistry. 2020 Mar 3;59(8):955-963. doi: 10.1021/acs.biochem.9b01072. Epub, 2020 Feb 12. PMID:31999437 doi:http://dx.doi.org/10.1021/acs.biochem.9b01072

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/6nkr"

@@ Line 3: / Line 3: @@
 <StructureSection load='6nkr' size='340' side='right'caption='[[6nkr]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6nkr]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NKR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NKR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6nkr]] 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=6NKR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6NKR FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DGT:2-DEOXYGUANOSINE-5-TRIPHOSPHATE'>DGT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DGT:2-DEOXYGUANOSINE-5-TRIPHOSPHATE'>DGT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DOC:2,3-DIDEOXYCYTIDINE-5-MONOPHOSPHATE'>DOC</scene></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=6nkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkr OCA], [http://pdbe.org/6nkr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nkr RCSB], [http://www.ebi.ac.uk/pdbsum/6nkr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkr ProSAT]</span></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://proteopedia.org/fgij/fg.htm?mol=6nkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nkr OCA], [http://pdbe.org/6nkr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nkr RCSB], [http://www.ebi.ac.uk/pdbsum/6nkr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nkr ProSAT]</span></td></tr>
 </table>
 == Function ==
 [[http://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 human DNA polymerase (pol) beta cancer variant K289M has altered polymerase activity in vitro, and the structure of wild-type pol beta reveals that the K289 side chain contributes to a network of stabilizing interactions in a C-terminal region of the enzyme distal to the active site. Here, we probed the capacity of the K289M variant to tolerate strain introduced within the C-terminal region and active site. Strain was imposed by making use of a dGTP analogue containing a CF2 group substitution for the beta-gamma bridging oxygen atom. The ternary complex structure of the K289M variant displays an alteration in the C-terminal region, whereas the structure of wild-type pol beta is not altered in the presence of the dGTP CF2 analogue. The alteration in the K289M variant impacts the active site, because the enzyme in the ternary complex fails to adopt the normal open to closed conformational change and assembly of the catalytically competent active site. These results reveal the importance of the K289-mediated stabilizing network in the C-terminal region of pol beta and suggest an explanation for why the K289M cancer variant is deficient in polymerase activity even though the position 289 side chain is distal to the active site.
+Revealing an Internal Stabilization Deficiency in the DNA Polymerase beta K289M Cancer Variant through the Combined Use of Chemical Biology and X-ray Crystallography.,Batra VK, Alnajjar KS, Sweasy JB, McKenna CE, Goodman MF, Wilson SH Biochemistry. 2020 Mar 3;59(8):955-963. doi: 10.1021/acs.biochem.9b01072. Epub, 2020 Feb 12. PMID:31999437<ref>PMID:31999437</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6nkr" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[DNA polymerase 3D structures|DNA polymerase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Batra, V K]]

6nkr

From Proteopedia

Revision as of 11:21, 22 July 2020

Ternary complex crystal structure of K289M variant of DNA polymerase Beta with dGTP

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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