5IXA: Hcmv Dna Polymerase Processivity Subunit Ul44 At Neutral Ph And Low Salt

Citation:
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.
PDB ID: 5IXADownload
MMDB ID: 145249
PDB Deposition Date: 2016/3/23
Updated in MMDB: 2016/12
Experimental Method:
x-ray diffraction
Resolution: 2.68  Å
Source Organism:
Similar Structures:
Biological Unit for 5IXA: dimeric; determined by author and by software (PISA)
Molecular Components in 5IXA
Label Count Molecule
Proteins (2 molecules)
2
DNA Polymerase Processivity Factor
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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