5IXA

HCMV DNA polymerase processivity subunit UL44 at neutral pH and low salt

5IXA の概要

• エントリーDOI: 10.2210/pdb5ixa/pdb
• 関連するPDBエントリー: 1T6L 1YYP 5IWD
• 分子名称: DNA polymerase processivity factor (2 entities in total)
• 機能のキーワード: hcmv pol accessory subunit, protein-protein interaction, human cytomegalovirus, dna polymerase, processivity factor, replication
• 由来する生物種: Human cytomegalovirus (strain AD169) (HHV-5)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65153.01

構造登録者

Chen, H.,Coen, D.M.,Hogle, J.M.,Filman, D.J. (登録日: 2016-03-23, 公開日: 2016-11-30, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.684 Å)