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- EMDB-21247: A 2.8 Angstrom Cryo-EM Structure of a Glycoprotein B-Neutralizing... -

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Basic information

Entry
Database: EMDB / ID: EMD-21247
TitleA 2.8 Angstrom Cryo-EM Structure of a Glycoprotein B-Neutralizing Antibody Complex Reveals a Critical Domain for Herpesvirus Fusion Initiation
Map dataVaricella zoster virus human neutralizing antibody, 93k, in complex with native gB
Sample
  • Complex: Varicella zoster virus glycoprotein B in complex with Fab fragments derived from human monoclonal antibody 93k
    • Complex: human monoclonal antibody 93k Fab
      • Protein or peptide: Human monoclonal antibody 93k variable light chain
      • Protein or peptide: Human monoclonal antibody 93k variable heavy chain
    • Complex: Varicella zoster virus glycoprotein B
      • Protein or peptide: Envelope glycoprotein B
Function / homology
Function and homology information


host cell Golgi membrane / host cell endosome membrane / membrane => GO:0016020 / symbiont entry into host cell / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane
Similarity search - Function
TonB-dependent receptor (TBDR) proteins signature 1. / 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 / Envelope glycoprotein B
Similarity search - Component
Biological speciesHomo sapiens (human) / Human herpesvirus 3 (Varicella-zoster virus) / HHV-3, Varicella zoster virus, Human alphaherpesvirus 3
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsOliver SL
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01A102546 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM079429 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P41GM103832 United States
National Institutes of Health/Office of the DirectorS10OD021600 United States
CitationJournal: Nat Commun / Year: 2020
Title: A glycoprotein B-neutralizing antibody structure at 2.8 Å uncovers a critical domain for herpesvirus fusion initiation.
Authors: Stefan L Oliver / Yi Xing / Dong-Hua Chen / Soung Hun Roh / Grigore D Pintilie / David A Bushnell / Marvin H Sommer / Edward Yang / Andrea Carfi / Wah Chiu / Ann M Arvin /
Abstract: Members of the Herpesviridae, including the medically important alphaherpesvirus varicella-zoster virus (VZV), induce fusion of the virion envelope with cell membranes during entry, and between cells ...Members of the Herpesviridae, including the medically important alphaherpesvirus varicella-zoster virus (VZV), induce fusion of the virion envelope with cell membranes during entry, and between cells to form polykaryocytes in infected tissues. The conserved glycoproteins, gB, gH and gL, are the core functional proteins of the herpesvirus fusion complex. gB serves as the primary fusogen via its fusion loops, but functions for the remaining gB domains remain unexplained. As a pathway for biological discovery of domain function, our approach used structure-based analysis of the viral fusogen together with a neutralizing antibody. We report here a 2.8 Å cryogenic-electron microscopy structure of native gB recovered from VZV-infected cells, in complex with a human monoclonal antibody, 93k. This high-resolution structure guided targeted mutagenesis at the gB-93k interface, providing compelling evidence that a domain spatially distant from the gB fusion loops is critical for herpesvirus fusion, revealing a potential new target for antiviral therapies.
History
DepositionJan 29, 2020-
Header (metadata) releaseMar 25, 2020-
Map releaseJul 15, 2020-
UpdateNov 25, 2020-
Current statusNov 25, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6vn1
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21247.png

Downloads & links

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Map

FileDownload / File: emd_21247.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationVaricella zoster virus human neutralizing antibody, 93k, in complex with native gB
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.025
Minimum - Maximum-0.16648911 - 0.22452323
Average (Standard dev.)-0.00001424307 (±0.003540269)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 407.03998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z407.040407.040407.040
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-0.1660.225-0.000

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Supplemental data

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Half map: half map 1

Fileemd_21247_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_21247_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Varicella zoster virus glycoprotein B in complex with Fab fragmen...

EntireName: Varicella zoster virus glycoprotein B in complex with Fab fragments derived from human monoclonal antibody 93k
Components
  • Complex: Varicella zoster virus glycoprotein B in complex with Fab fragments derived from human monoclonal antibody 93k
    • Complex: human monoclonal antibody 93k Fab
      • Protein or peptide: Human monoclonal antibody 93k variable light chain
      • Protein or peptide: Human monoclonal antibody 93k variable heavy chain
    • Complex: Varicella zoster virus glycoprotein B
      • Protein or peptide: Envelope glycoprotein B

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Supramolecule #1: Varicella zoster virus glycoprotein B in complex with Fab fragmen...

SupramoleculeName: Varicella zoster virus glycoprotein B in complex with Fab fragments derived from human monoclonal antibody 93k
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightExperimental: 750 KDa

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Supramolecule #2: human monoclonal antibody 93k Fab

SupramoleculeName: human monoclonal antibody 93k Fab / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: Varicella zoster virus glycoprotein B

SupramoleculeName: Varicella zoster virus glycoprotein B / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Human herpesvirus 3 (Varicella-zoster virus)

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Macromolecule #1: Human monoclonal antibody 93k variable light chain

MacromoleculeName: Human monoclonal antibody 93k variable light chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.826245 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIQMTQSPST LSASVGDRVT ITCRASQTIS TWLAWYQQTP RKAPKLMIYK ASILENGVPS RFSGSGSGTE FTLTISSLQP EDFATYYCQ QYKSYPWTFG QGTKVEI

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Macromolecule #2: Human monoclonal antibody 93k variable heavy chain

MacromoleculeName: Human monoclonal antibody 93k variable heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.658357 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLVQSGAE VKKPGSSVKV SCKASGGTFS NFAISWVRQA PGQGLEWMGR IMPLFVTSTY AQKFQGRVTI SADASTSTAY MELSSLRSD DTAMYYCARD ITAPGAAPTP LNFYGMDVWG QGTTVTVSS

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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: HHV-3, Varicella zoster virus, Human alphaherpesvirus 3
Molecular weightTheoretical: 105.50232 KDa
SequenceString: MSPCGYYSKW RNRDRPEYRR NLRFRRFFSS IHPNAAAGSG FNGPGVFITS VTGVWLCFLC IFSMFVTAVV SVSPSSFYES LQVEPTQSE DITRSAHLGD GDEIREAIHK SQDAETKPTF YVCPPPTGST IVRLEPPRTC PDYHLGKNFT EGIAVVYKEN I AAYKFKAT ...String:
MSPCGYYSKW RNRDRPEYRR NLRFRRFFSS IHPNAAAGSG FNGPGVFITS VTGVWLCFLC IFSMFVTAVV SVSPSSFYES LQVEPTQSE DITRSAHLGD GDEIREAIHK SQDAETKPTF YVCPPPTGST IVRLEPPRTC PDYHLGKNFT EGIAVVYKEN I AAYKFKAT VYYKDVIVST AWAGSSYTQI TNRYADRVPI PVSEITDTID KFGKCSSKAT YVRNNHKVEA FNEDKNPQDM PL IASKYNS VGSKAWHTTN DTYMVAGTPG TYRTGTSVNC IIEEVEARSI FPYDSFGLST GDIIYMSPFF GLRDGAYREH SNY AMDRFH QFEGYRQRDL DTRALLEPAA RNFLVTPHLT VGWNWKPKRT EVCSLVKWRE VEDVVRDEYA HNFRFTMKTL STTF ISETN EFNLNQIHLS QCVKEEARAI INRIYTTRYN SSHVRTGDIQ TYLARGGFVV VFQPLLSNSL ARLYLQELVR ENTNH SPQK HPTRNTRSRR SVPVELRANR TITTTSSVEF AMLQFTYDHI QEHVNEMLAR ISSSWCQLQN RERALWSGLF PINPSA LAS TILDQRVKAR ILGDVISVSN CPELGSDTRI ILQNSMRVSG STTRCYSRPL ISIVSLNGSG TVEGQLGTDN ELIMSRD LL EPCVANHKRY FLFGHHYVYY EDYRYVREIA VHDVGMISTY VDLNLTLLKD REFMPLRVYT RDELRDTGLL DYSEIQRR N QMHSLRFYDI DKVVQYDSGT AIMQGMAQFF QGLGTAGQAV GHVVLGATGA LLSTVHGFTT FLSNPFGALA VGLLVLAGL VAAFFAYRYV LKLKTSPMKA LYPLTTKGLK QLPEGMDPFA EKPNATDTPI EEIGDSQNTE PSVNSGFDPD KFREAQEMIK YMTLVSAAE RQESKARKKN KTSALLTSRL TGLALRNRRG YSRVRTENVT GV

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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: 7.4
GridDetails: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 98 % / Chamber temperature: 298 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 4 / Number real images: 11283 / Average exposure time: 12.0 sec. / Average electron dose: 7.5 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: 1.5 µm / Nominal magnification: 130000
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 correctionSoftware - Name: CTFFIND
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 856068
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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