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- EMDB-46760: Cryo-EM structure of neutralizing human antibody D48 in complex w... -

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Basic information

Entry
Database: EMDB / ID: EMD-46760
TitleCryo-EM structure of neutralizing human antibody D48 in complex with HSV-1 glycoprotein B trimer gB-Ecto.516P
Map data
Sample
  • Complex: D48 in complex with HSV-1 gB ectodomain trimer
    • Protein or peptide: Glycoprotein B
    • Protein or peptide: D48 heavy chain
    • Protein or peptide: D48 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsimmune complex / neutralization / herpes fusogen / VIRAL PROTEIN
Function / homology
Function and homology information


host cell endosome / host cell Golgi apparatus / viral envelope / symbiont entry into host cell / virion attachment to host cell / host cell plasma membrane / membrane
Similarity search - Function
: / Herpesvirus Glycoprotein B / Herpesvirus Glycoprotein B, PH-like domain 1 / Herpesvirus Glycoprotein B, PH-like domain 2 / Herpesvirus Glycoprotein B, PH-like domain 2 superfamily / Herpesvirus Glycoprotein B ectodomain / Herpesvirus Glycoprotein B / Herpesvirus Glycoprotein B PH-like domain
Similarity search - Domain/homology
Biological speciesHuman alphaherpesvirus 1 (Herpes simplex virus type 1) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsRoark RS / Shapiro L / Kwong PD
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Nat Microbiol / Year: 2025
Title: Prefusion structure, evasion and neutralization of HSV-1 glycoprotein B.
Authors: Ryan S Roark / Andrew J Schaub / Wei Shi / Maple Wang / Fabiana A Bahna / Jordan E Becker / Andrea Biju / Sue Chong / Haijuan Du / Yicheng Guo / Hsiang Hong / Phinikoula S Katsamba / Seetha ...Authors: Ryan S Roark / Andrew J Schaub / Wei Shi / Maple Wang / Fabiana A Bahna / Jordan E Becker / Andrea Biju / Sue Chong / Haijuan Du / Yicheng Guo / Hsiang Hong / Phinikoula S Katsamba / Seetha M Mannepalli / Adam S Olia / Li Ou / Sarah K Rubin / Yosef Sabo / Mehin Suleiman / Malcolm L Wells / Baoshan Zhang / Cheng Cheng / Anum Glasgow / David D Ho / Yaoxing Huang / Theodore C Pierson / Reda Rawi / Tongqing Zhou / Lawrence Shapiro / Peter D Kwong /
Abstract: Glycoprotein B (gB) refolds between prefusion and postfusion conformations to facilitate herpesvirus entry into host cells. However, the isolation of prefusion-specific neutralizing antibodies, ...Glycoprotein B (gB) refolds between prefusion and postfusion conformations to facilitate herpesvirus entry into host cells. However, the isolation of prefusion-specific neutralizing antibodies, effective against other viral entry machines, has been challenging. Here we describe stabilization of the prefusion gB ectodomain from herpes simplex virus 1 (HSV-1), determine ectodomain structures at 2.9- to 4.1-Å resolution using cryogenic electron microscopy (cryo-EM) and isolate a prefusion-specific gB-neutralizing antibody termed WS.HSV-1.24. Murine immunization with gB stabilized in the prefusion conformation induced high titres of antibodies binding to both prefusion and postfusion gB, but-most notably-without measurable serum neutralization. Accessibility analysis revealed iso-surface exposure, with accessible surfaces on prefusion HSV-1 gB also exposed on postfusion gB. Structural analysis suggested substantial plasticity, with regions that refolded between pre- and postfusion conformations relegated to domain interfaces with limited accessibility; indeed, WS.HSV-1.24 recognized a domain-interface refolding region to facilitate neutralization. We propose that prefusion HSV-1 gB evades neutralization by most antibodies through an iso-surface display that is coupled to structural plasticity.
History
DepositionAug 27, 2024-
Header (metadata) releaseSep 10, 2025-
Map releaseSep 10, 2025-
UpdateNov 12, 2025-
Current statusNov 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46760.png

Downloads & links

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Map

FileDownload / File: emd_46760.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 400 pix.
= 332. Å		0.83 Å/pix.
x 400 pix.
= 332. Å		0.83 Å/pix.
x 400 pix.
= 332. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.18124843 - 0.45101115
Average (Standard dev.)0.0023391617 (±0.013482279)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 332.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_46760_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_46760_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : D48 in complex with HSV-1 gB ectodomain trimer

EntireName: D48 in complex with HSV-1 gB ectodomain trimer
Components
  • Complex: D48 in complex with HSV-1 gB ectodomain trimer
    • Protein or peptide: Glycoprotein B
    • Protein or peptide: D48 heavy chain
    • Protein or peptide: D48 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: D48 in complex with HSV-1 gB ectodomain trimer

SupramoleculeName: D48 in complex with HSV-1 gB ectodomain trimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Human alphaherpesvirus 1 (Herpes simplex virus type 1)

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Macromolecule #1: Glycoprotein B

MacromoleculeName: Glycoprotein B / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human alphaherpesvirus 1 (Herpes simplex virus type 1)
Molecular weightTheoretical: 90.304141 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MHQGAPSWGR RWFVVWALLG LTLGVLVASA APSSPGTPGV AAATQAANGG PATPAPPALG AAPTGDPKPK KNKKPKNPTP PRPAGDNAT VAAGHATLRE HLRDIKAENT DANFYVCPPP TGATVVQFEQ PRRCPTRPEG QNYTEGIAVV FKENIAPYKF K ATMYYKDV ...String:
MHQGAPSWGR RWFVVWALLG LTLGVLVASA APSSPGTPGV AAATQAANGG PATPAPPALG AAPTGDPKPK KNKKPKNPTP PRPAGDNAT VAAGHATLRE HLRDIKAENT DANFYVCPPP TGATVVQFEQ PRRCPTRPEG QNYTEGIAVV FKENIAPYKF K ATMYYKDV TVSQVWFGHR YSQFMGIFED RAPVPFEEVI DKINAKGVCR STAKYVRNNL ETTAFHRDDH ETDMELKPAN AA TRTSRGW HTTDLKYNPS RVEAFHRYGT TVNCIVEEVD ARSVYPYDEF VLATGDFVYM SPFYGYREGS HTEHTSYAAD RFK QVDGFY ARDLTTKARA TAPTTRNLLT TPKFTVAWDW VPKRPSVCTM TKWQEVDEML RSEYGGSFRF SSDAISTTFT TNLT EYPLS RVDLGDCIGK DARDAMDRIF ARRYNATHIK VGQPQYYLAN GGFLIAYQPL LSNTLAELYV REHLREQSRK PPNPT PPPP GASANASVER IKTTSSIEFA RLQFTYNHIQ RPVNDMLGRV AIAWCELQNH ELTLWNEARK LNPNAIASVT VGRRVS ARM LGDVMAVSTC VPVAADNVIV QNSMRISSRP GACYSRPLVS FRYEDQGPLV EGQLGENNEL RLTRDAIEPC TVGHRRY FT FGGGYVYFEE YAYSHQLSRA DITTVSTFID LNITMLEDHE FVPLEVYTRH EIKDSGLLDY TEVQRRNQLH DLRFADID T VIHADANGSG YIPEAPRDGQ AYVRKDGEWV LLSTFLGRSL EVLFQGPGHH HHHHHHSAWS HPQFEKGGGS GGGGSGGSA WSHPQFEK

UniProtKB: Glycoprotein B

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Macromolecule #2: D48 heavy chain

MacromoleculeName: D48 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.601957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVETGGG VVRPGRSLRL SCTTSGFSFS GSAMHWVRQA PGKGLEWVAV ISHDGNIIQY HDSVKGRFTI SRDNSKNVLL LQMNSLRVD DTAMYYCARD VWLLPATISY AFDFWGQGTM VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
EVQLVETGGG VVRPGRSLRL SCTTSGFSFS GSAMHWVRQA PGKGLEWVAV ISHDGNIIQY HDSVKGRFTI SRDNSKNVLL LQMNSLRVD DTAMYYCARD VWLLPATISY AFDFWGQGTM VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCD KTHTLEVLFQ

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Macromolecule #3: D48 light chain

MacromoleculeName: D48 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.476164 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VIWMTQSPPS LSASIGDTVT ITCRASQGIS NSIAWYQRRP GKAPELLVYA AYRLQSGVPS RLSGSGSGAE YTLTIKNMQP EDFATYYCQ QYYDNPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
VIWMTQSPPS LSASIGDTVT ITCRASQGIS NSIAWYQRRP GKAPELLVYA AYRLQSGVPS RLSGSGSGAE YTLTIKNMQP EDFATYYCQ QYYDNPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

2gum

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 139193
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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