Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Viral DNA polymerase structures reveal mechanisms of antiviral drug resistance.
Journal, issue, pages	Cell, Vol. 187, Issue 20, Page 5572-5586.e15, Year 2024
Publish date	Aug 26, 2024
Authors	Sundaresh 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 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 ...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 links	Cell / PubMed:39197451
Methods	EM (single particle)
Resolution	2.7 - 5.1 Å
Structure data	28663 8exx 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 42887 8v1q 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 42888 8v1r 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 42889 8v1s 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 42890 8v1t 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, inhibitorYM 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)
Keywords	VIRAL 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