9NDZ

The rigid portion of Cryo-EM structure of Herpesvirus Helicase-Primase complex prepared with forked DNA, ATP-gamma-S and Pritelivir

Summary for 9NDZ

• Entry DOI: 10.2210/pdb9ndz/pdb
• EMDB information: 49290
• Descriptor: DNA primase, DNA helicase/primase complex-associated protein (2 entities in total)
• Functional Keywords: inhibitor, herpesvirus, helicase, primase, pritelivir, replication, transferase
• Biological source: Herpesviridae; More
• Total number of polymer chains: 2
• Total formula weight: 194608.29

Authors

Yao, Q.,Yu, X. (deposition date: 2025-02-19, release date: 2025-08-13, Last modification date: 2026-02-25)

Primary citation

Yao, Q.,Mercier, A.,Nayak, A.,May, L.,Ho, P.Y.,Lewis-Ballester, A.,Nair, V.,Sapre, A.,Aeschbacher, T.,Mukherjee, J.,Richards, C.,Mateo, R.,Cho, A.,Lansdon, E.,Yu, X.
Structural and mechanistic insights into herpesvirus helicase-primase and its therapeutic inhibitors.
Nat Microbiol, 10:3191-3201, 2025

PubMed Abstract: The herpes simplex virus (HSV) helicase-primase (HP) complex is a promising anti-herpes therapeutic target. However, progress in developing highly effective small-molecule HP inhibitors (HPIs) for the treatment of genital herpes has been hindered by the lack of structural information on the HP complex and the incomplete understanding of the mechanism of action of HPIs. Here we present the cryogenic electron microscopy structure of the HSV-1 HP apo-complex (3.8 Å), along with structures bound to pritelivir (3.2 Å) and amenamevir (3.2 Å)-two clinically active, chemically distinct HPIs. The potency of both inhibitors against HSV variants bearing mutations within the HPI binding pocket supports the high-resolution mapping of key molecular interactions while revealing residues that govern their antiviral spectrum against alphaherpesviruses. Our results provide important insight into the unique architecture of the HP complex and the mechanism of inhibition of HPIs, paving the way for the development of next-generation antivirals to treat herpesvirus infections.

PubMed: 41188384
DOI: 10.1038/s41564-025-02168-4

Experimental method

ELECTRON MICROSCOPY (3 Å)