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- PDB-9nel: The flexible portion of Cryo-EM structure of Herpesvirus Helicase... -

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Basic information

Entry
Database: PDB / ID: 9nel
TitleThe flexible portion of Cryo-EM structure of Herpesvirus Helicase-Primase complex with amenamevir
Components
  • DNA primase
  • DNA replication helicase
KeywordsREPLICATION / TRANSFERASE/INHIBITOR / Inhibitor / Herpesvirus / Helicase / Primase / Pritelivir / TRANSFERASE-INHIBITOR 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 replication helicase, Herpesvirus / Helicase / DNA primase / Herpesviridae UL52/UL70 DNA primase / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / DNA replication helicase / DNA primase
Similarity search - Component
Biological speciesHerpesviridae (virus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYao, Q. / Yu, X.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Microbiol / Year: 2025
Title: Structural and mechanistic insights into herpesvirus helicase-primase and its therapeutic inhibitors.
Authors: Qing Yao / Alexandre Mercier / Arabinda Nayak / Lindsey May / Pui Yan Ho / Ariel Lewis-Ballester / Varsha Nair / Annapurna Sapre / Thomas Aeschbacher / Jit Mukherjee / Christopher Richards / ...Authors: Qing Yao / Alexandre Mercier / Arabinda Nayak / Lindsey May / Pui Yan Ho / Ariel Lewis-Ballester / Varsha Nair / Annapurna Sapre / Thomas Aeschbacher / Jit Mukherjee / Christopher Richards / Roberto Mateo / Aesop Cho / Eric Lansdon / Xinchao Yu /
Abstract: The herpes simplex virus (HSV) helicase-primase (HP) complex is a promising anti-herpes therapeutic target. However, progress in developing highly effective small-molecule HP inhibitors (HPIs) for ...The herpes simplex virus (HSV) helicase-primase (HP) complex is a promising anti-herpes therapeutic target. However, progress in developing highly effective small-molecule HP inhibitors (HPIs) for the treatment of genital herpes has been hindered by the lack of structural information on the HP complex and the incomplete understanding of the mechanism of action of HPIs. Here we present the cryogenic electron microscopy structure of the HSV-1 HP apo-complex (3.8 Å), along with structures bound to pritelivir (3.2 Å) and amenamevir (3.2 Å)-two clinically active, chemically distinct HPIs. The potency of both inhibitors against HSV variants bearing mutations within the HPI binding pocket supports the high-resolution mapping of key molecular interactions while revealing residues that govern their antiviral spectrum against alphaherpesviruses. Our results provide important insight into the unique architecture of the HP complex and the mechanism of inhibition of HPIs, paving the way for the development of next-generation antivirals to treat herpesvirus infections.
History
DepositionFeb 19, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release
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Revision 1.1Feb 25, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA primase
B: DNA replication helicase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)209,8393
Polymers209,3562
Non-polymers4831
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein DNA primase


Mass: 114602.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Herpesviridae (virus) / Gene: UL52 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10236, Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases
#2: Protein DNA replication helicase


Mass: 94753.688 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Herpesviridae (virus) / Gene: HELI, UL5 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P10189, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
#3: Chemical ChemComp-A1BXD / Amenamevir


Mass: 482.552 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N4O5S / Feature type: SUBJECT OF INVESTIGATION
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: The ternary complex of HSV-1 UL8/UL52/UL5 helicase-primase complex
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Herpesviridae (virus)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 298 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM software
IDNameVersionCategory
11cryoSPARC2.11final Euler assignment
13RELION53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 115543 / Symmetry type: POINT

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