9HGI

HSV-1 Origin Binding Protein in complex with double-stranded DNA recognition sequence OriS with 6 basepairs removed from the AT-rich region

Summary for 9HGI

• Entry DOI: 10.2210/pdb9hgi/pdb
• EMDB information: 52135
• Descriptor: Replication origin-binding protein, DNA (5'-D(P*TP*AP*TP*TP*GP*GP*GP*AP*CP*GP*AP*AP*GP*TP*GP*CP*GP*AP*AP*CP*GP*CP*TP*T)-3'), DNA (5'-D(P*AP*AP*GP*CP*GP*TP*TP*CP*GP*CP*AP*CP*TP*TP*CP*GP*TP*CP*CP*CP*AP*AP*TP*A)-3') (3 entities in total)
• Functional Keywords: dna, helicase, complex, dna binding protein
• Biological source: Human alphaherpesvirus 1 strain KOS; More
• Total number of polymer chains: 4
• Total formula weight: 236989.39

Authors

Gustavsson, E.,Grunewald, K.,Elias, P.,Hallberg, B.M. (deposition date: 2024-11-19, release date: 2025-10-22, Last modification date: 2025-11-05)

Primary citation

Gustavsson, E.,Grunewald, K.,Elias, P.,Hallberg, B.M.
The herpes simplex origin-binding protein: mechanisms for sequence-specific DNA binding and dimerization revealed by Cryo-EM.
Nucleic Acids Res., 53:-, 2025

PubMed 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.

PubMed: 41125242
DOI: 10.1093/nar/gkaf1029

Experimental method

ELECTRON MICROSCOPY (2.77 Å)