5iwd
HCMV DNA polymerase subunit UL44 complex with a small molecule
Structural highlights
FunctionVPAP_HCMVA Accessory subunit of the DNA polymerase that acts to increase the processivity of polymerization.[1] Publication Abstract from PubMedHuman 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
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