8V1T
Herpes simplex virus 1 polymerase holoenzyme bound to DNA and acyclovir triphosphate in closed conformation
Summary for 8V1T
| Entry DOI | 10.2210/pdb8v1t/pdb |
| EMDB information | 28663 28664 42887 42888 42889 42890 42891 |
| Descriptor | DNA polymerase, DNA polymerase processivity factor, PRIMER DNA (32-MER), ... (7 entities in total) |
| Functional Keywords | herpes simplex virus, replication, dna polymerase, acyclovir, antiherpesvirus drug, transferase-dna complex, transferase/dna |
| Biological source | Human alphaherpesvirus 1 strain KOS More |
| Total number of polymer chains | 4 |
| Total formula weight | 195589.01 |
| Authors | Pan, J.,Abraham, J.,Coen, D.M.,Shankar, S.,Yang, P.,Hogle, J. (deposition date: 2023-11-21, release date: 2024-09-04, Last modification date: 2024-10-16) |
| Primary citation | 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 Cited by 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: 39197451DOI: 10.1016/j.cell.2024.07.048 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
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