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- EMDB-26520: Post-fusion ectodomain of HSV-1 gB in complex with BMPC-23 Fab -

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Open data


ID or keywords:

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Basic information

Entry
Database: EMDB / ID: EMD-26520
TitlePost-fusion ectodomain of HSV-1 gB in complex with BMPC-23 Fab
Map dataHSV-1 gB in complex with BMPC23 Fab
Sample
  • Complex: Trimeric HSV-1 gB in complex with three BCMP-23 Fabs
    • Protein or peptide: BMPC-23 Fab Heavy chain
    • Protein or peptide: BMPC-23 Fab Light chain
    • Protein or peptide: Envelope glycoprotein B
Function / homology
Function and homology information


host cell Golgi membrane / host cell endosome membrane / symbiont entry into host cell / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / membrane / identical protein binding
Similarity search - Function
Herpesvirus Glycoprotein B ectodomain / Herpesvirus Glycoprotein B / Herpesvirus Glycoprotein B, PH-like domain 1 / Herpesvirus Glycoprotein B, PH-like domain 2 / Herpesvirus Glycoprotein B / Herpesvirus Glycoprotein B PH-like domain / Herpesvirus Glycoprotein B, PH-like domain 2 superfamily
Similarity search - Domain/homology
Envelope glycoprotein B
Similarity search - Component
Biological speciesMus musculus (house mouse) / Human alphaherpesvirus 1 strain KOS
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsWindsor IW / Kong SL / Garforth SJ / Almo SC / Harrison SC
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: J Clin Invest / Year: 2023
Title: A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice.
Authors: Masayuki Kuraoka / Clare Burn Aschner / Ian W Windsor / Aakash Mahant Mahant / Scott J Garforth / Susan Luozheng Kong / Jacqueline M Achkar / Steven C Almo / Garnett Kelsoe / Betsy C Herold /
Abstract: There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, ...There is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, ΔgD-2, demonstrated that non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of ΔgD-2-vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcγR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcγRIV, a biomarker of ADCC. The cryo-electron microscopic structure of the Fab-glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcγRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV.
History
DepositionMar 28, 2022-
Header (metadata) releaseFeb 8, 2023-
Map releaseFeb 8, 2023-
UpdateFeb 15, 2023-
Current statusFeb 15, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26520.png

Downloads & links

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Map

FileDownload / File: emd_26520.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHSV-1 gB in complex with BMPC23 Fab
Voxel sizeX=Y=Z: 0.825 Å
Density
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.024537351 - 0.039906744
Average (Standard dev.)3.7255904e-06 (±0.0010407447)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 369.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map 2

Fileemd_26520_half_map_1.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_26520_half_map_2.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Trimeric HSV-1 gB in complex with three BCMP-23 Fabs

EntireName: Trimeric HSV-1 gB in complex with three BCMP-23 Fabs
Components
  • Complex: Trimeric HSV-1 gB in complex with three BCMP-23 Fabs
    • Protein or peptide: BMPC-23 Fab Heavy chain
    • Protein or peptide: BMPC-23 Fab Light chain
    • Protein or peptide: Envelope glycoprotein B

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Supramolecule #1: Trimeric HSV-1 gB in complex with three BCMP-23 Fabs

SupramoleculeName: Trimeric HSV-1 gB in complex with three BCMP-23 Fabs / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: BMPC-23 Fab Heavy chain

MacromoleculeName: BMPC-23 Fab Heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.425734 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLQQSGPE LVKPGASVKL SCKASGYSFT TYDINWVKER PGQGLEWIGW IYPREGSTNY NEKFRGKATL TADTSSSTAY MELHSLTSE DSAVYFCATY GSSRYYTMDY WGQGTSVTVS SA

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Macromolecule #2: BMPC-23 Fab Light chain

MacromoleculeName: BMPC-23 Fab Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.072557 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIVLTQSPTS LAVSLGQRAT ISCRASESVD NFGISFMNWF QQKPGQPPKL LIYAASNLGS GVPARFSGSG SGTDFSLNIH PMEDDDTAM YFCQQSKEVP LTFGAGTKLE LKR

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Macromolecule #3: Envelope glycoprotein B

MacromoleculeName: Envelope glycoprotein B / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human alphaherpesvirus 1 strain KOS / Strain: KOS
Molecular weightTheoretical: 71.668188 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DIKAENTDAN FYVCPPPTGA TVVQFEQPRR CPTRPEGQNY TEGIAVVFKE NIAPYKFKAT MYYKDVTVSQ VWFGHRYSQF MGIFEDRAP VPFEEVIDKI NAKGVCRSTA KYVRNNLETT AFHRDDHETD MELKPANAAT RTSRGWHTTD LKYNPSRVEA F HRYGTTVN ...String:
DIKAENTDAN FYVCPPPTGA TVVQFEQPRR CPTRPEGQNY TEGIAVVFKE NIAPYKFKAT MYYKDVTVSQ VWFGHRYSQF MGIFEDRAP VPFEEVIDKI NAKGVCRSTA KYVRNNLETT AFHRDDHETD MELKPANAAT RTSRGWHTTD LKYNPSRVEA F HRYGTTVN CIVEEVDARS VYPYDEFVLA TGDFVYMSPF YGYREGSHTE HTTYAADRFK QVDGFYARDL TTKARATAPT TR NLLTTPK FTVAWDWVPK RPSVCTMTKW QEVDEMLRSE YGGSFRFSSD AISTTFTTNL TEYPLSRVDL GDCIGKDARD AMD RIFARR YNATHIKVGQ PQYYQANGGF LIAYQPLLSN TLAELYVREH LREQSRKPPN PTPPPPGASA NASVERIKTT SSIE FARLQ FTYNHIQRHV NDMLGRVAIA WCELQNHELT LWNEARKLNP NAIASVTVGR RVSARMLGDV MAVSTCVPVA ADNVI VQNS MRISSRPGAC YSRPLVSFRY EDQGPLVEGQ LGENNELRLT RDAIEPCTVG HRRYFTFGGG YVYFEEYAYS HQLSRA DIT TVSTFIDLNI TMLEDHEFVP LEVYTRHEIK DSGLLDYTEV QRRNQLHDLR FADIDTVIHA DANAA

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 55.8 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 218056
FSC plot (resolution estimation)

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