Journal Article

PUBDB-2025-04614

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The herpes simplex origin-binding protein: mechanisms for sequence-specific DNA binding and dimerization revealed by Cryo-EM

Gustavsson, E.CSSB*DESY* ; Grünewald, K.CSSB*DESY* ; Elias, P. ; Hällberg, B. M. (Corresponding author)

2025
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/nar/gkaf1029  doi:10.3204/PUBDB-2025-04614

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.

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)

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Contributing Institute(s):

1. CSSB - Leibniz-Institut für Experimentelle Virologie (LIV) - Kay Grünewald (CSSB-LIV-KG)
2. Institut Karolinska / Sweden (KI)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)
2. DFG project G:(GEPRIS)534044797 - Large Scale Data Facility 3 - Anteil Forschungsgroßgerät (LSDF3-FuGG) (534044797) (534044797)

Experiment(s):

1. (Multi-User Cryo-EM Facility)
2. (Protein Production Core Facility)

Appears in the scientific report 2025

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Database coverage:
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