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| | ==HCMV DNA polymerase processivity subunit UL44 at neutral pH and low salt== | | ==HCMV DNA polymerase processivity subunit UL44 at neutral pH and low salt== |
| - | <StructureSection load='5ixa' size='340' side='right' caption='[[5ixa]], [[Resolution|resolution]] 2.68Å' scene=''> | + | <StructureSection load='5ixa' size='340' side='right'caption='[[5ixa]], [[Resolution|resolution]] 2.68Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ixa]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IXA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IXA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ixa]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_herpesvirus_5_strain_AD169 Human herpesvirus 5 strain AD169]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IXA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IXA FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1yyp|1yyp]], [[1t6l|1t6l]], [[5iwd|5iwd]]</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]] 2.684Å</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=5ixa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ixa OCA], [http://pdbe.org/5ixa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ixa RCSB], [http://www.ebi.ac.uk/pdbsum/5ixa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ixa ProSAT]</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=5ixa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ixa OCA], [https://pdbe.org/5ixa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ixa RCSB], [https://www.ebi.ac.uk/pdbsum/5ixa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ixa ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/VPAP_HCMVA VPAP_HCMVA]] Accessory subunit of the DNA polymerase that acts to increase the processivity of polymerization.<ref>PMID:20538862</ref> | + | [https://www.uniprot.org/uniprot/VPAP_HCMVA VPAP_HCMVA] Accessory subunit of the DNA polymerase that acts to increase the processivity of polymerization.<ref>PMID:20538862</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chen, H]] | + | [[Category: Human herpesvirus 5 strain AD169]] |
| - | [[Category: Coen, D M]] | + | [[Category: Large Structures]] |
| - | [[Category: Filman, D J]] | + | [[Category: Chen H]] |
| - | [[Category: Hogle, J M]] | + | [[Category: Coen DM]] |
| - | [[Category: Dna polymerase]] | + | [[Category: Filman DJ]] |
| - | [[Category: Hcmv pol accessory subunit]] | + | [[Category: Hogle JM]] |
| - | [[Category: Human cytomegalovirus]]
| + | |
| - | [[Category: Processivity factor]]
| + | |
| - | [[Category: Protein-protein interaction]]
| + | |
| - | [[Category: Replication]]
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| Structural highlights
Function
VPAP_HCMVA Accessory subunit of the DNA polymerase that acts to increase the processivity of polymerization.[1]
Publication Abstract from PubMed
Human cytomegalovirus DNA polymerase comprises a catalytic subunit, UL54, and an accessory subunit, UL44, the interaction of which may serve as a target for the development of new antiviral drugs. Using a high-throughput screen, we identified a small molecule, (5-((dimethylamino)methylene-3-(methylthio)-6,7-dihydrobenzo[c]thiophen-4(5H)-one ), that selectively inhibits the interaction of UL44 with a UL54-derived peptide in a time-dependent manner, full-length UL54, and UL44-dependent long-chain DNA synthesis. A crystal structure of the compound bound to UL44 revealed a covalent reaction with lysine residue 60 and additional noncovalent interactions that cause steric conflicts that would prevent the UL44 connector loop from interacting with UL54. Analyses of the reaction of the compound with model substrates supported a resonance-stabilized conjugation mechanism, and substitution of the lysine reduced the ability of the compound to inhibit UL44-UL54 peptide interactions. This novel covalent inhibitor of polymerase subunit interactions may serve as a starting point for new, needed drugs to treat human cytomegalovirus infections.
A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions.,Chen H, Coseno M, Ficarro SB, Mansueto MS, Komazin-Meredith G, Boissel S, Filman DJ, Marto JA, Hogle JM, Coen DM ACS Infect Dis. 2017 Feb 10;3(2):112-118. doi: 10.1021/acsinfecdis.6b00079. Epub , 2016 Dec 6. PMID:28183184[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kim YE, Ahn JH. Role of the specific interaction of UL112-113 p84 with UL44 DNA polymerase processivity factor in promoting DNA replication of human cytomegalovirus. J Virol. 2010 Sep;84(17):8409-21. doi: 10.1128/JVI.00189-10. Epub 2010 Jun 10. PMID:20538862 doi:http://dx.doi.org/10.1128/JVI.00189-10
- ↑ Chen H, Coseno M, Ficarro SB, Mansueto MS, Komazin-Meredith G, Boissel S, Filman DJ, Marto JA, Hogle JM, Coen DM. A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions. ACS Infect Dis. 2017 Feb 10;3(2):112-118. doi: 10.1021/acsinfecdis.6b00079. Epub , 2016 Dec 6. PMID:28183184 doi:http://dx.doi.org/10.1021/acsinfecdis.6b00079
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