5IWD

HCMV DNA polymerase subunit UL44 complex with a small molecule

Summary for 5IWD

• Entry DOI: 10.2210/pdb5iwd/pdb
• Related: 1T6L 1YYP 5IXA
• Descriptor: DNA polymerase processivity factor, 5-methylidene-3-(methylsulfanyl)-2-benzothiophen-4(5H)-one (3 entities in total)
• Functional Keywords: covalent inhibitor, hcmv pol accessory subunit, protein-protein interaction, human cytomegalovirus, dna polymerase, processivity factor, replication-replication inhibitor complex, replication/replication inhibitor
• Biological source: Human cytomegalovirus (strain AD169) (HHV-5)
• Total number of polymer chains: 1
• Total formula weight: 33215.39

Authors

Chen, H.,Coen, D.M.,Hogle, J.M.,Filman, D.J. (deposition date: 2016-03-22, release date: 2016-11-30, Last modification date: 2024-10-16)

Primary citation

Chen, H.,Coseno, M.,Ficarro, S.B.,Mansueto, M.S.,Komazin-Meredith, G.,Boissel, S.,Filman, D.J.,Marto, J.A.,Hogle, J.M.,Coen, D.M.
A Small Covalent Allosteric Inhibitor of Human Cytomegalovirus DNA Polymerase Subunit Interactions.
ACS Infect Dis, 3:112-118, 2017

PubMed Abstract: 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.

PubMed: 28183184
DOI: 10.1021/acsinfecdis.6b00079

Experimental method

X-RAY DIFFRACTION (2.56 Å)