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@ARTICLE{Gustavsson:613884,
author = {Gustavsson, Emil and Grünewald, Kay and Elias, Per and
Hällberg, B Martin},
title = {{D}ynamics of the {H}erpes simplex virus {DNA} polymerase
holoenzyme during {DNA} synthesis and proof-reading revealed
by {C}ryo-{EM}},
journal = {Nucleic acids symposium series},
volume = {52},
number = {12},
issn = {0305-1048},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {PUBDB-2024-05663},
pages = {7292-7304},
year = {2024},
note = {The CryoEM Facility at CSSB is supported by the UHH and DFG
[INST 152/772-1|152/774-1|152/775-1|152/776-1|152/777-1
FUGG].},
abstract = {Herpes simplex virus 1 (HSV-1), a double-stranded DNA
virus, replicates using seven essential proteins encoded by
its genome. Among these, the UL30 DNA polymerase, complexed
with the UL42 processivity factor, orchestrates leading and
lagging strand replication of the 152 kb viral genome. UL30
polymerase is a prime target for antiviral therapy, and
resistance to current drugs can arise in immunocompromised
individuals. Using electron cryo-microscopy (cryo-EM), we
unveil the dynamic changes of the UL30/UL42 complex with DNA
in three distinct states. First, a pre-translocation state
with an open fingers domain ready for nucleotide
incorporation. Second, a halted elongation state where the
fingers close, trapping dATP in the dNTP pocket. Third, a
DNA-editing state involving significant conformational
changes to allow DNA realignment for exonuclease activity.
Additionally, the flexible UL30 C-terminal domain interacts
with UL42, forming an extended positively charged surface
binding to DNA, thereby enhancing processive synthesis.
These findings highlight substantial structural shifts in
the polymerase and its DNA interactions during replication,
offering insights for future antiviral drug development.},
cin = {FS-CS / CSSB-LIV-KG},
ddc = {540},
cid = {I:(DE-H253)FS-CS-20210408 /
I:(DE-H253)CSSB-LIV-KG-20220525},
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-MLZ)NOSPEC-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:38806233},
UT = {WOS:001233236800001},
doi = {10.1093/nar/gkae374},
url = {https://bib-pubdb1.desy.de/record/613884},
}