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TitleViral DNA polymerase structures reveal mechanisms of antiviral drug resistance.
Journal, issue, pagesCell, Vol. 187, Issue 20, Page 5572-5586.e15, Year 2024
Publish dateOct 3, 2024
AuthorsSundaresh Shankar / Junhua Pan / Pan Yang / Yuemin Bian / Gábor Oroszlán / Zishuo Yu / Purba Mukherjee / David J Filman / James M Hogle / Mrinal Shekhar / Donald M Coen / Jonathan Abraham /
PubMed AbstractDNA 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 ...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.
External linksCell / PubMed:39197451
MethodsEM (single particle)
Resolution2.7 - 5.1 Å
Structure data

EMDB-28663, PDB-8exx:
Herpes simplex virus 1 polymerase holoenzyme bound to DNA and foscarnet (pre-translocation state)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-28664: Herpes simplex virus 1 DNA polymerase holoenzyme bound to DNA template and primer, dNTP-free (editing mode)
Method: EM (single particle) / Resolution: 3.77 Å

EMDB-42887, PDB-8v1q:
Herpes simplex virus 1 polymerase holoenzyme bound to DNA in both open/closed conformations
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-42888, PDB-8v1r:
Herpes simplex virus 1 polymerase holoenzyme bound to DNA and DTTP in closed conformation
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-42889, PDB-8v1s:
Herpes simplex virus 1 polymerase holoenzyme bound to mismatched DNA in editing conformation
Method: EM (single particle) / Resolution: 3.26 Å

EMDB-42890, PDB-8v1t:
Herpes simplex virus 1 polymerase holoenzyme bound to DNA and acyclovir triphosphate in closed conformation
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-42891: Herpes simplex virus 1 polymerase W781V mutant holoenzyme bound to DNA in editing conformation
Method: EM (single particle) / Resolution: 5.1 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-PPF:
PHOSPHONOFORMIC ACID / medication, antivirus, inhibitor*YM

ChemComp-HOH:
WATER

ChemComp-TTP:
THYMIDINE-5'-TRIPHOSPHATE

ChemComp-AVP:
ACYCLOVIR TRIPHOSPHATE

Source
  • Human herpesvirus 1 (strain KOS)
  • human alphaherpesvirus 1 strain kos
  • synthetic construct (others)
KeywordsVIRAL PROTEIN/DNA / herpes simplex virus / replication / DNA polymerase holoenzyme / UL30 / UL42 / pre-translocation / foscarnet / VIRAL PROTEIN / VIRAL PROTEIN-DNA complex / TRANSFERASE/DNA / open/closed conformations / conformational dynamics / TRANSFERASE-DNA complex / closed conformation / editing conformation / DNA polymerase / ACYCLOVIR / antiherpesvirus drug

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