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- PDB-9nn2: Composite structure of HSV-1 helicase-primase in complex with a f... -

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Basic information

Entry
Database: PDB / ID: 9nn2
TitleComposite structure of HSV-1 helicase-primase in complex with a forked DNA and amenamevir
Components
  • DNA (5'-D(P*AP*TP*CP*TP*GP*TP*T)-3')
  • DNA helicase/primase complex-associated protein
  • DNA primase
  • DNA replication helicase
KeywordsTransferase/Hydrolase / DNA replication / HSV-1 helicase-primase / VIRAL PROTEIN / Transferase-Hydrolase complex
Function / homology
Function and homology information


bidirectional double-stranded viral DNA replication / helicase activity / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / DNA-directed RNA polymerase activity / DNA replication / hydrolase activity / host cell nucleus / zinc ion binding / ATP binding
Similarity search - Function
DNA replication helicase domain / DNA helicase/primase complex-associated protein / DNA replication helicase, Herpesvirus / Herpesvirus DNA helicase/primase complex associated protein / Helicase / DNA primase / Herpesviridae UL52/UL70 DNA primase / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / DNA / DNA (> 10) / DNA replication helicase / DNA helicase/primase complex-associated protein / DNA primase
Similarity search - Component
Biological speciesHuman alphaherpesvirus 1 strain 17
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsHe, Q. / Baranovskiy, A.G. / Morstadt, L.M. / Babayeva, N.D. / Lim, C. / Tahirov, T.H.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM152032 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)DP2GM150023 United States
CitationJournal: Sci Adv / Year: 2025
Title: Structural basis of herpesvirus helicase-primase inhibition by pritelivir and amenamevir.
Authors: Andrey G Baranovskiy / Qixiang He / Yoshiaki Suwa / Lucia M Morstadt / Nigar D Babayeva / Ci Ji Lim / Tahir H Tahirov /
Abstract: Widespread herpesvirus infections are associated with various diseases. DNA replication of human herpes simplex virus type 1 (HSV-1) requires a helicase-primase (HP) complex of three core proteins: ...Widespread herpesvirus infections are associated with various diseases. DNA replication of human herpes simplex virus type 1 (HSV-1) requires a helicase-primase (HP) complex of three core proteins: UL5, UL52, and UL8. This complex unwinds viral DNA and synthesizes primers for DNA replication, making it an attractive antiviral target. Although HP inhibitors pritelivir and amenamevir were identified through screening, their binding mechanisms remain unclear. Here, we report cryo-electron microscopy structures of HSV-1 HP bound to a forked DNA template alone and in complex with pritelivir or amenamevir. The structures reveal a bilobed architecture highlighting HP coordinated action at the replication fork and providing a structural basis for HP inhibition by illustrating precisely how pritelivir and amenamevir block helicase activity. Data lay a solid foundation for the development of improved antiviral therapies.
History
DepositionMar 4, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 19, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
D: DNA (5'-D(P*AP*TP*CP*TP*GP*TP*T)-3')
A: DNA replication helicase
B: DNA primase
C: DNA helicase/primase complex-associated protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)304,0537
Polymers303,4394
Non-polymers6133
Water724
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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DNA chain , 1 types, 1 molecules D

#1: DNA chain DNA (5'-D(P*AP*TP*CP*TP*GP*TP*T)-3')


Mass: 13114.381 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Protein , 3 types, 3 molecules ABC

#2: Protein DNA replication helicase


Mass: 95760.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human alphaherpesvirus 1 strain 17 / Gene: HELI, UL5 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P10189, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
#3: Protein DNA primase


Mass: 114558.562 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human alphaherpesvirus 1 strain 17 / Gene: UL52 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P10236, Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases
#4: Protein DNA helicase/primase complex-associated protein / HEPA / Primase-associated factor


Mass: 80005.664 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human alphaherpesvirus 1 strain 17 / Gene: UL8 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P10192

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Non-polymers , 3 types, 7 molecules

#5: Chemical ChemComp-A1BXD / Amenamevir


Mass: 482.552 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N4O5S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: HSV-1 helicase-primase in complex with a forked DNA and amenamevir
Type: COMPLEX
Details: HSV-1 helicase-primase in complex with a forked DNA and amenamevir sovled using cryo-EM single-particle analysis
Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.3 MDa / Experimental value: NO
Source (natural)Organism: Human alphaherpesvirus 1 strain 17
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
Details: CHAPSO is made fresh at 80 mM before being added to the sample at a final concentration of 2 mM immediately before vitrification
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acidHEPES1
2100 mMpotassium chlorideKCl1
30.5 percentGlycerolGlycerol1
42 mMdithiothreitolDTT1
52 mMCHAPSOCHAPSO1
SpecimenConc.: 5.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: The sample was monodisperse
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 12660

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Processing

EM software
IDNameVersionCategory
4cryoSPARCCTF correction
7Cootmodel fitting
9cryoSPARCinitial Euler assignment
12cryoSPARC3D reconstruction
13PHENIX1.21_5207:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4689246
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 725691 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingSource name: AlphaFold / Type: in silico model
RefinementHighest resolution: 3.1 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00320024
ELECTRON MICROSCOPYf_angle_d0.43427333
ELECTRON MICROSCOPYf_dihedral_angle_d6.9422900
ELECTRON MICROSCOPYf_chiral_restr0.0383078
ELECTRON MICROSCOPYf_plane_restr0.0043552

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