Summary information and primary citation
- PDB-id
-
8exx;
SNAP-derived features in text and
JSON formats
- Class
- viral protein-DNA
- Method
- cryo-EM (3.3 Å)
- Summary
- Herpes simplex virus 1 polymerase holoenzyme bound to
DNA and foscarnet (pre-translocation state)
- Reference
-
Shankar S, Pan J, Yang P, Bian Y, Oroszlan G, Yu Z,
Mukherjee P, Filman DJ, Hogle JM, Shekhar M, Coen DM,
Abraham J (2024): "Viral DNA
polymerase structures reveal mechanisms of antiviral drug
resistance." Cell, 187,
5572-5586.e15. doi: 10.1016/j.cell.2024.07.048.
- Abstract
- DNA polymerases are important drug targets, and many
structural studies have captured them in distinct
conformations. However, a detailed understanding of the
impact of polymerase conformational dynamics on drug
resistance is lacking. We determined cryoelectron
microscopy (cryo-EM) structures of DNA-bound herpes simplex
virus polymerase holoenzyme in multiple conformations and
interacting with antivirals in clinical use. These
structures reveal how the catalytic subunit Pol and the
processivity factor UL42 bind DNA to promote processive DNA
synthesis. Unexpectedly, in the absence of an incoming
nucleotide, we observed Pol in multiple conformations with
the closed state sampled by the fingers domain. Drug-bound
structures reveal how antivirals may selectively bind
enzymes that more readily adopt the closed conformation.
Molecular dynamics simulations and the cryo-EM structure of
a drug-resistant mutant indicate that some resistance
mutations modulate conformational dynamics rather than
directly impacting drug binding, thus clarifying mechanisms
that drive drug selectivity.
