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@ARTICLE{Gustavsson:639657,
author = {Gustavsson, Emil and Grünewald, Kay and Elias, Per and
Hällberg, B Martin},
title = {{T}he herpes simplex origin-binding protein: mechanisms for
sequence-specific {DNA} binding and dimerization revealed by
{C}ryo-{EM}},
journal = {Nucleic acids symposium series},
volume = {53},
number = {19},
issn = {0305-1048},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {PUBDB-2025-04614},
pages = {gkaf1029},
year = {2025},
note = {ISSN 1362-4962 not unique: **2 hits**. DFG grant numbers
(INST 152/772-1|152/774-1|152/775-1|152/776-1|152/777-1
FUGG)},
abstract = {Herpes simplex viruses 1 and 2 (HSV-1,2) present growing
treatment challenges due to increasing resistance to
antivirals targeting viral DNA polymerase, particularly in
immunocompromised individuals. The HSV-1 origin-binding
protein (OBP), an essential Superfamily 2 (SF2) DNA helicase
encoded by the UL9 gene, is a promising alternative
therapeutic target. Here, we present cryo-EM structures of
OBP at up to 2.8 Å resolution in multiple conformational
states, including complexes with the OriS recognition
sequence and the non-hydrolyzable ATP analog ATPγS. The
structures reveal an unexpected head-to-tail dimer
stabilized by the C-terminal domain, where the conserved
RVKNL motif mediates sequence-specific DNA recognition. The
C-terminal domain extends into the partner monomer,
suggesting a regulatory mechanism involving the
single-stranded DNA-binding protein ICP8. We also resolve an
OBP monomer bound to a DNA hairpin with a 3′
single-stranded tail (mini-OriS*), and at lower resolution,
a dimer-dimer assembly of two OBP dimers bound
simultaneously to OriS or mini-OriS*. These structures
uncover the molecular basis of HSV-1 origin recognition and
unwinding, and identify multiple druggable interfaces,
laying the groundwork for structure-based antiviral
development targeting HSV-1 OBP.},
cin = {CSSB-LIV-KG / KI},
ddc = {540},
cid = {I:(DE-H253)CSSB-LIV-KG-20220525 / I:(DE-H253)KI-20130912},
pnm = {633 - Life Sciences – Building Blocks of Life: Structure
and Function (POF4-633) / DFG project G:(GEPRIS)534044797 -
Large Scale Data Facility 3 - Anteil Forschungsgroßgerät
(LSDF3-FuGG) (534044797)},
pid = {G:(DE-HGF)POF4-633 / G:(GEPRIS)534044797},
experiment = {EXP:(DE-H253)cryo-EM-20250101 / EXP:(DE-H253)PP-20250101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41125242},
doi = {10.1093/nar/gkaf1029},
url = {https://bib-pubdb1.desy.de/record/639657},
}