9YCT

HSV helicase-primase complex bound to pritelivir

This is a non-PDB format compatible entry.

Summary for 9YCT

• Entry DOI: 10.2210/pdb9yct/pdb
• Related: 9P6L
• EMDB information: 72786
• Descriptor: DNA (5'-D(*TP*TP*TP*TP*TP*T)-3'), UL52, UL5, ... (6 entities in total)
• Functional Keywords: hsv, helicase-primase, pritelivir, viral protein
• Biological source: Human alphaherpesvirus 1 strain R-15; More
• Total number of polymer chains: 4
• Total formula weight: 295635.57

Authors

Yu, Z.,Abraham, J. (deposition date: 2025-09-19, release date: 2025-12-31, Last modification date: 2026-07-15)

Primary citation

Yu, Z.,Sathyanarayana, P.,Liu, C.,Tan, J.M.J.,Yang, P.,Das, B.,Hu, S.,Fan, X.,Ji, C.,Weller, S.K.,Shekhar, M.,Coen, D.M.,Kranzusch, P.J.,Loparo, J.J.,Abraham, J.
Mechanisms of HSV-1 helicase-primase inhibition and replication fork complex assembly.
Cell, 189:478-494.e18, 2026

PubMed Abstract: Herpesviruses are widespread double-stranded DNA viruses that establish lifelong latency and cause various diseases. Although DNA-polymerase-targeting antivirals are effective, increasing drug resistance underscores the need for alternatives. Helicase-primase inhibitors (HPIs) are promising antivirals, but their mechanisms of action are poorly defined. Furthermore, how the helicase-primase (H/P) complex and DNA polymerase coordinate genome replication is not well understood for herpesviruses. Here, we report cryo-electron microscopy (cryo-EM) structures of the herpes simplex virus 1 H/P complex bound to HPIs, showing that these lock the H/P complex in an inactive state. Single-molecule assays reveal that HPIs cause H/P complexes to pause in unwinding activity on DNA. The structure of an HPI-bound replication fork complex, comprising the H/P complex (UL5, UL52, and UL8) and the polymerase holoenzyme (UL30 and UL42), reveals a previously uncharacterized interface bridging these complexes. These findings provide a structural framework for understanding herpesvirus replisome assembly and advancing inhibitor development.

PubMed: 41468884
DOI: 10.1016/j.cell.2025.11.041

Experimental method

ELECTRON MICROSCOPY (3.7 Å)