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TitleStructural insights into HSV-1 origin unwinding by the viral proteins UL9 and ICP8.
Journal, issue, pagesNucleic Acids Res, Vol. 54, Issue 11, Year 2026
Publish dateJun 8, 2026
AuthorsAndrey G Baranovskiy / Lucia M Morstadt / Eduardo E Romero / Nigar D Babayeva / Tahir H Tahirov /
PubMed AbstractHerpes simplex virus type 1 (HSV-1) causes lifelong infections in human cells and is associated with a range of diseases. HSV-1 DNA replication requires seven viral proteins, including the major DNA- ...Herpes simplex virus type 1 (HSV-1) causes lifelong infections in human cells and is associated with a range of diseases. HSV-1 DNA replication requires seven viral proteins, including the major DNA-binding protein ICP8, the origin-binding protein UL9, and proteins that comprise the helicase-primase and DNA polymerase complexes. UL9 functions as a DNA helicase that specifically recognizes and binds to the viral origins of replication, OriS and OriL. Here we report the cryo-EM structure of the UL9/ICP8/DNA/ATPγS complex at an overall resolution of 3.18 Å. This structure revealed that UL9 employs an α-helix to separate the DNA strands and captures the initial step of OriS unwinding, in which the C-terminal domain of UL9 specifically binds to the major groove of a DNA double helix, while the N-terminal helicase domain engages the unwound leading and lagging strands. ICP8 interacts with the extreme C-terminal region of UL9, preventing UL9 dimerization. Simultaneously, it binds and stabilizes the leading-strand DNA adjacent to UL9. Together, these findings provide mechanistic insight into UL9-driven DNA unwinding and the cooperative action of UL9 and ICP8 at HSV-1 replication origins, establishing a structural framework for the rational interpretation of prior biochemical data and for the design of new antiviral drugs.
External linksNucleic Acids Res / PubMed:42283126 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.2 Å
Structure data

EMDB-74143: The sharpened consensus map for UL9-ICP8-DNA complex
Method: EM (single particle) / Resolution: 3.18 Å

EMDB-74144: The focused map for ICP8-DNA
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-74145: The focused map for UL9-DNA
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-74190, PDB-9zgf:
The complex of HSV-1 proteins UL9 and ICP8 with forked DNA
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

Source
  • human alphaherpesvirus 1 strain 17
KeywordsREPLICATION/DNA / DNA replication / protein-DNA complex / REPLICATION-DNA complex

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