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- EMDB-49276: The rigid portion of Cryo-EM structure of Herpesvirus Helicase-Pr... -

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Basic information

Entry
Database: EMDB / ID: EMD-49276
TitleThe rigid portion of Cryo-EM structure of Herpesvirus Helicase-Primase complex prepared with forked DNA and ATP-gamma-S
Map data
Sample
  • Complex: The ternary complex of HSV-1 UL8/UL52/UL5 helicase-primase
    • Protein or peptide: DNA primase
    • Protein or peptide: DNA helicase/primase complex-associated protein
KeywordsHelicase / Primase / Herpesvirus / REPLICATION / TRANSFERASE
Function / homology
Function and homology information


bidirectional double-stranded viral DNA replication / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / DNA-directed RNA polymerase activity / DNA replication / host cell nucleus / zinc ion binding
Similarity search - Function
DNA helicase/primase complex-associated protein / Herpesvirus DNA helicase/primase complex associated protein / DNA primase / Herpesviridae UL52/UL70 DNA primase
Similarity search - Domain/homology
DNA helicase/primase complex-associated protein / DNA primase
Similarity search - Component
Biological speciesHerpesviridae (virus)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsYao Q / Yu X
Funding support1 items
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 18, 2025-
Header (metadata) releaseAug 13, 2025-
Map releaseAug 13, 2025-
UpdateFeb 25, 2026-
Current statusFeb 25, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49276.png

Downloads & links

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Map

FileDownload / File: emd_49276.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 420 pix.
= 306.18 Å		0.73 Å/pix.
x 420 pix.
= 306.18 Å		0.73 Å/pix.
x 420 pix.
= 306.18 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.729 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0854
Minimum - Maximum-0.0018000165 - 1.8466303
Average (Standard dev.)0.00049890135 (±0.01593783)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions420420420
Spacing420420420
CellA=B=C: 306.18 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_49276_msk_1.map
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AxesZYX

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Half map: #1

Fileemd_49276_half_map_1.map
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Half map: #2

Fileemd_49276_half_map_2.map
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Sample components

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Entire : The ternary complex of HSV-1 UL8/UL52/UL5 helicase-primase

EntireName: The ternary complex of HSV-1 UL8/UL52/UL5 helicase-primase
Components
  • Complex: The ternary complex of HSV-1 UL8/UL52/UL5 helicase-primase
    • Protein or peptide: DNA primase
    • Protein or peptide: DNA helicase/primase complex-associated protein

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Supramolecule #1: The ternary complex of HSV-1 UL8/UL52/UL5 helicase-primase

SupramoleculeName: The ternary complex of HSV-1 UL8/UL52/UL5 helicase-primase
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Herpesviridae (virus)

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Macromolecule #1: DNA primase

MacromoleculeName: DNA primase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases
Source (natural)Organism: Herpesviridae (virus)
Molecular weightTheoretical: 114.427352 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GQEDGNRGER RAAGTPVEVT ALYATDGCVI TSSIALLTNS LLGAEPVYIF SYDAYTHDGR ADGPTEQDRF EESRALYQAS GGLNGDSFR VTFCLLGTEV GGTHQARGRT RPMFVCRFER ADDVAALQDA LAHGTPLQPD HIAATLDAEA TFALHANMIL A LTVAINNA ...String:
GQEDGNRGER RAAGTPVEVT ALYATDGCVI TSSIALLTNS LLGAEPVYIF SYDAYTHDGR ADGPTEQDRF EESRALYQAS GGLNGDSFR VTFCLLGTEV GGTHQARGRT RPMFVCRFER ADDVAALQDA LAHGTPLQPD HIAATLDAEA TFALHANMIL A LTVAINNA SPRTGRDAAA AQYDQGASLR SLVGRTSLGQ RGLTTLYVHH EVRVLAAYRR AYYGSAQSPF WFLSKFGPDE KS LVLTTRY YLLQAQRLGG AGATYDLQAI KDICATYAIP HAPRPDTVSA ASLTSFAAIT RFCCTSQYAR GAAAAGFPLY VER RIAADV RETSALEKFI THDRSCLRVS DREFITYIYL AHFECFSPPR LATHLRAVTT HDPNPAASTE QPSPLGREAV EQFF CHVRA QLNIGEYVKH NVTPRETVLD GDTAKAYLRA RTYAPGALTP APAYCGAVDS ATKMMGRLAD AEKLLVPRGW PAFAP ASPG EDTAGGTPPP QTCGIVKRLL RLAATEQQGP TPPAIAALIR NAAVQTPLPV YRISMVPTGQ AFAALAWDDW ARITRD ARL AEAVVSAEAA AHPDHGALGR RLTDRIRAQG PVMPPGGLDA GGQMYVNRNE IFNGALAITN IILDLDIALK EPVPFRR LH EALGHFRRGA LAAVQLLFPA ARVDPDAYPC YFFKSACRPG PASVGSGSGL GNDDDGDWFP CYDDAGDEEW AEDPGAMD T SHDPPDDEVA YFDLCHEVGP TAEPRETDSP VCSCTDKIGL RVCMPVPAPY VVHGSLTMRG VARVIQQAVL LDRDFVEAI GSYVKNFLLI DTGVYAHGHS LRLPYFAKIA PDGPACGRLL PVFVIPPACK DVPAFVAAHA DPRRFHFHAP PTYLASPREI RVLHSLGGD YVSFFERKAS RNALEHFGRR ETLTEVLGRY NVQPDAGGTV EGFASELLGR IVACIETHFP EHAGEYQAVS V RRAVSKDD WVLLQLVPVR GTLQQSLSCL RFKHGRASRA TARTFVALSV GANNRLCVSL CQQCFAAKCD SNRLHTLFTI DA GTPCSPS VPCSTSQPSS

UniProtKB: DNA primase

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Macromolecule #2: DNA helicase/primase complex-associated protein

MacromoleculeName: DNA helicase/primase complex-associated protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Herpesviridae (virus)
Molecular weightTheoretical: 79.704336 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDTADIVWVE ESVSAITLYA VWLPPAREYF HALVYFVCRN AAGEGRARFA EVSVTATELR DFYGSADVSV QAVVAAARAA TTPAASPLE PLENPTLWRA LYACVLAALE RQTGPVALFA PLRIGSDPRT GLVVKVERAW GPPAAPRAAL LVAEANIDID P MALAARVA ...String:
MDTADIVWVE ESVSAITLYA VWLPPAREYF HALVYFVCRN AAGEGRARFA EVSVTATELR DFYGSADVSV QAVVAAARAA TTPAASPLE PLENPTLWRA LYACVLAALE RQTGPVALFA PLRIGSDPRT GLVVKVERAW GPPAAPRAAL LVAEANIDID P MALAARVA EHPDARLAWA RLAAIRDTPQ CASAASLTVN ITTGTALFAR EYQTLAFPPI KKEGAFGDLV EVCEVGLRPR GH PQRVTAR VLLPRDYDYF VSAGEKFSAP ALVALFRQWH TTVHAAPALA PVFAFLGPEF EVRGGPVPYF AVLGFPGWPT FTV PATAES ARDLVRGAAA AYAALLGAWP AVGARVVLPP RAWPGVASAA AGCLLPAVRE AVARWHPATK IIQLLDPPAA VGPV WTARF CFPGLRAQLL AALADLGGSG LADPHGRTGL ARLDALVVAA PSEPWAGAVL ERLVPDTCNA CPALRQLLGG VMAAV CLQI EETASSVKFA VCGGDGGAFW GVFNVDPQDA DAASGVIEDA RRAIETAVGA VLRANAVRLR HPLCLALEGV YTHAVA WSQ AGVWFWNSRD NTDHLGGFPL RGPAYTTAAG VVRDTLRRVL GLTTACVPEE DALTARGLME DACDRLILDA FNKRLDA EY WSVRVSPFEA SDPLPPTAFR GGALLDAEHY WRRVVRVCPG GGESVGVPVD LYPRPLVLPP VDCAHHLREI LREIELVF T GVLAGVWGEG GKFVYPFDDK MSFLFA

UniProtKB: DNA helicase/primase complex-associated protein

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 52547
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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