8V1Q

Herpes simplex virus 1 polymerase holoenzyme bound to DNA in both open/closed conformations

8V1Q の概要

• エントリーDOI: 10.2210/pdb8v1q/pdb
• EMDBエントリー: 28663 28664 42887 42888 42889 42890 42891
• 分子名称: DNA polymerase, DNA polymerase processivity factor, Primer DNA, ... (6 entities in total)
• 機能のキーワード: herpes simplex virus, dna polymerase holoenzyme, open/closed conformations, conformational dynamics, transferase-dna complex, transferase/dna
• 由来する生物種: Human alphaherpesvirus 1 strain KOS; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 196028.21

構造登録者

Pan, J.,Abraham, J.,Coen, D.M.,Shankar, S.,Yang, P.,Hogle, J. (登録日: 2023-11-21, 公開日: 2024-09-04, 最終更新日: 2024-10-16)

主引用文献

Shankar, S.,Pan, J.,Yang, P.,Bian, Y.,Oroszlan, G.,Yu, Z.,Mukherjee, P.,Filman, D.J.,Hogle, J.M.,Shekhar, M.,Coen, D.M.,Abraham, J.
Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance.
Cell, 187:5572-5586.e15, 2024

PubMed 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.

PubMed: 39197451
DOI: 10.1016/j.cell.2024.07.048

実験手法

ELECTRON MICROSCOPY (2.7 Å)