5u2s: Difference between revisions
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==Pre-catalytic ternary complex of Human DNA Polymerase Beta With Gapped DNA substrate incoming (-)3TC-TP and Ca2+.== | |||
<StructureSection load='5u2s' size='340' side='right'caption='[[5u2s]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5u2s]] 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=5U2S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U2S FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RZ:[[(2R,5S)-5-(4-AZANYL-2-OXIDANYLIDENE-PYRIMIDIN-1-YL)-1,3-OXATHIOLAN-2-YL]METHOXY-OXIDANYL-PHOSPHORYL]+PHOSPHONO+HYDROGEN+PHOSPHATE'>1RZ</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <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=5u2s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u2s OCA], [https://pdbe.org/5u2s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u2s RCSB], [https://www.ebi.ac.uk/pdbsum/5u2s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u2s 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Nucleoside reverse transcriptase inhibitors (NRTIs) with L-stereochemistry have long been an effective treatment for viral infections because of the strong D-stereoselectivity exhibited by human DNA polymerases relative to viral reverse transcriptases. The D-stereoselectivity of DNA polymerases has only recently been explored structurally and all three DNA polymerases studied to date have demonstrated unique stereochemical selection mechanisms. Here, we have solved structures of human DNA polymerase beta (hPolbeta), in complex with single-nucleotide gapped DNA and L-nucleotides and performed pre-steady-state kinetic analysis to determine the D-stereoselectivity mechanism of hPolbeta. Beyond a similar 180 degrees rotation of the L-nucleotide ribose ring seen in other studies, the pre-catalytic ternary crystal structures of hPolbeta, DNA and L-dCTP or the triphosphate forms of antiviral drugs lamivudine ((-)3TC-TP) and emtricitabine ((-)FTC-TP) provide little structural evidence to suggest that hPolbeta follows the previously characterized mechanisms of D-stereoselectivity. Instead, hPolbeta discriminates against L-stereochemistry through accumulation of several active site rearrangements that lead to a decreased nucleotide binding affinity and incorporation rate. The two NRTIs escape some of the active site selection through the base and sugar modifications but are selected against through the inability of hPolbeta to complete thumb domain closure. | |||
Structural basis for the D-stereoselectivity of human DNA polymerase beta.,Vyas R, Reed AJ, Raper AT, Zahurancik WJ, Wallenmeyer PC, Suo Z Nucleic Acids Res. 2017 Apr 10. doi: 10.1093/nar/gkx252. PMID:28402499<ref>PMID:28402499</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5u2s" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[DNA polymerase 3D structures|DNA polymerase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Suo Z]] | |||
[[Category: Vyas R]] | |||
Latest revision as of 16:18, 4 October 2023
Pre-catalytic ternary complex of Human DNA Polymerase Beta With Gapped DNA substrate incoming (-)3TC-TP and Ca2+.Pre-catalytic ternary complex of Human DNA Polymerase Beta With Gapped DNA substrate incoming (-)3TC-TP and Ca2+.
Structural highlights
FunctionDPOLB_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 PubMedNucleoside reverse transcriptase inhibitors (NRTIs) with L-stereochemistry have long been an effective treatment for viral infections because of the strong D-stereoselectivity exhibited by human DNA polymerases relative to viral reverse transcriptases. The D-stereoselectivity of DNA polymerases has only recently been explored structurally and all three DNA polymerases studied to date have demonstrated unique stereochemical selection mechanisms. Here, we have solved structures of human DNA polymerase beta (hPolbeta), in complex with single-nucleotide gapped DNA and L-nucleotides and performed pre-steady-state kinetic analysis to determine the D-stereoselectivity mechanism of hPolbeta. Beyond a similar 180 degrees rotation of the L-nucleotide ribose ring seen in other studies, the pre-catalytic ternary crystal structures of hPolbeta, DNA and L-dCTP or the triphosphate forms of antiviral drugs lamivudine ((-)3TC-TP) and emtricitabine ((-)FTC-TP) provide little structural evidence to suggest that hPolbeta follows the previously characterized mechanisms of D-stereoselectivity. Instead, hPolbeta discriminates against L-stereochemistry through accumulation of several active site rearrangements that lead to a decreased nucleotide binding affinity and incorporation rate. The two NRTIs escape some of the active site selection through the base and sugar modifications but are selected against through the inability of hPolbeta to complete thumb domain closure. Structural basis for the D-stereoselectivity of human DNA polymerase beta.,Vyas R, Reed AJ, Raper AT, Zahurancik WJ, Wallenmeyer PC, Suo Z Nucleic Acids Res. 2017 Apr 10. doi: 10.1093/nar/gkx252. PMID:28402499[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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