Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance

TY - JOUR

T1 - Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance

AU - Shankar, Sundaresh

AU - Pan, Junhua

AU - Yang, Pan

AU - Bian, Yuemin

AU - Oroszlán, Gábor

AU - Yu, Zishuo

AU - Mukherjee, Purba

AU - Filman, David J

AU - Hogle, James M

AU - Shekhar, Mrinal

AU - Coen, Donald M

AU - Abraham, Jonathan

N1 - © 2024 The Author(s)

PY - 2024/10/3

Y1 - 2024/10/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2024.07.048

DO - 10.1016/j.cell.2024.07.048

M3 - Article

C2 - 39197451

SN - 0092-8674

VL - 187

JO - Cell

JF - Cell

ER -