View source for 3kd1


==Closed binary complex of an RB69 gp43 fingers domain mutant complexed with an acyclic GMP terminated primer template pair.==
<StructureSection load='3kd1' size='340' side='right'caption='[[3kd1]], [[Resolution|resolution]] 2.66&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3kd1]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Bpr69 Bpr69]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KD1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KD1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=4DG:2-[(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)METHOXY]ETHYL+DIHYDROGEN+PHOSPHATE'>4DG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3kd5|3kd5]]</div></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">43, RB69 gp43 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=12353 BPR69])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3kd1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kd1 OCA], [https://pdbe.org/3kd1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3kd1 RCSB], [https://www.ebi.ac.uk/pdbsum/3kd1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3kd1 ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/DPOL_BPR69 DPOL_BPR69]] This polymerase possesses two enzymatic activities: DNA synthesis (polymerase) and an exonucleolytic activity that degrades single stranded DNA in the 3'- to 5'-direction. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phosphonoformic acid (PFA, foscarnet) belongs to a class of antiviral drugs that inhibit the human cytomegalovirus DNA polymerase (UL54) by mimicking the pyrophosphate leaving group of the nucleotide transfer reaction. Difficulties expressing UL54 have hampered investigation of the precise structural requirements rendering inhibition by this drug. However, a previously engineered chimeric DNA polymerase, constructed by mutating the homologous polymerase from bacteriophage RB69 (gp43) to express several variable elements from UL54, can bypass this obstacle because of its favorable expression and acquired sensitivity to PFA (Tchesnokov, E. P., Obikhod, A., Schinazi, R. F., and Gotte, M. (2008) J. Biol. Chem. 283, 34218-34228). Here, we compare two crystal structures that depict the chimeric DNA polymerase with and without PFA bound. PFA is visualized for the first time in the active site of a DNA polymerase, where interactions are resolved between the PP(i) mimic and two basic residues absolutely conserved in the fingers domain of family B polymerases. PFA also chelates metal ion B, the cation that contacts the triphosphate tail of the incoming nucleotide. These DNA complexes utilize a primer-template pair enzymatically chain-terminated by incorporation of acyclo-GMP, the phosphorylated form of the anti-herpes drug acyclovir. We postulate that the V478W mutation present in the chimera is critical in that it pushes the fingers domain to more readily adopt the closed conformation whether or not the drug is bound. The closed state of the fingers domain traps the variant polymerase in the untranslocated state and increases affinity for PFA. This finding provides a model for the mechanism of UL54 stalling by PFA.

Phosphonoformic acid inhibits viral replication by trapping the closed form of the DNA polymerase.,Zahn KE, Tchesnokov EP, Gotte M, Doublie S J Biol Chem. 2011 Jul 15;286(28):25246-55. doi: 10.1074/jbc.M111.248864. Epub, 2011 May 12. PMID:21566148<ref>PMID:21566148</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3kd1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bpr69]]
[[Category: DNA-directed DNA polymerase]]
[[Category: Large Structures]]
[[Category: Doublie, S]]
[[Category: Zahn, K E]]
[[Category: Acyclic guanosine]]
[[Category: Acyclovir]]
[[Category: Dna replication]]
[[Category: Dna-binding]]
[[Category: Dna-directed dna polymerase]]
[[Category: Exonuclease]]
[[Category: Foscarnet]]
[[Category: Foscavir]]
[[Category: Gp43]]
[[Category: Hcmv]]
[[Category: Human cytomegalovirus]]
[[Category: Hydrolase]]
[[Category: Nuclease]]
[[Category: Nucleotidyltransferase]]
[[Category: Phosphonoformic acid]]
[[Category: Polymerase]]
[[Category: Transferase]]
[[Category: Transferase-dna complex]]