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- PDB-6vn1: A 2.8 Angstrom Cryo-EM Structure of a Glycoprotein B-Neutralizing... -

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Basic information

Entry
Database: PDB / ID: 6vn1
TitleA 2.8 Angstrom Cryo-EM Structure of a Glycoprotein B-Neutralizing Antibody Complex Reveals a Critical Domain for Herpesvirus Fusion Initiation
Components
  • Envelope glycoprotein B
  • Human monoclonal antibody 93k variable heavy chain
  • Human monoclonal antibody 93k variable light chain
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Varicella Zoster Virus / Glycoprotein B / Neutralization / Monoclonal Antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex
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
Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #3280 / SH3 type barrels. - #1230 / PH-domain like - #100 / TonB-dependent receptor (TBDR) proteins signature 1. / 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 ...Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #3280 / SH3 type barrels. - #1230 / PH-domain like - #100 / TonB-dependent receptor (TBDR) proteins signature 1. / 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 / PH-domain like / Single alpha-helices involved in coiled-coils or other helix-helix interfaces / Helix non-globular / Special / SH3 type barrels. / Roll / Mainly Beta
Similarity search - Domain/homology
Envelope glycoprotein B / Envelope glycoprotein B
Similarity search - Component
Biological speciesHomo sapiens (human)
Human alphaherpesvirus 3 (Varicella-zoster virus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsOliver, S.L.
Funding support United States, 4items
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)P41GM103832 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM079429 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, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

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  • Deposited structure unit
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Structure viewerMolecule:
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Assembly

Deposited unit
L: Human monoclonal antibody 93k variable light chain
H: Human monoclonal antibody 93k variable heavy chain
A: Envelope glycoprotein B
M: Human monoclonal antibody 93k variable light chain
I: Human monoclonal antibody 93k variable heavy chain
B: Envelope glycoprotein B
N: Human monoclonal antibody 93k variable light chain
J: Human monoclonal antibody 93k variable heavy chain
C: Envelope glycoprotein B


Theoretical massNumber of molelcules
Total (without water)392,9619
Polymers392,9619
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: immunoprecipitation, native gel electrophoresis, gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area47900 Å2
ΔGint-260 kcal/mol
Surface area102710 Å2

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Components

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


Mass: 11826.245 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody Human monoclonal antibody 93k variable heavy chain


Mass: 13658.357 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Protein Envelope glycoprotein B / gB


Mass: 105502.320 Da / Num. of mol.: 3 / Source method: isolated from a natural source
Source: (natural) Human alphaherpesvirus 3 (Varicella-zoster virus)
References: UniProt: A0A1B1JGG9, UniProt: P09257*PLUS

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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

Component
IDNameTypeEntity IDParent-IDSource
1Varicella zoster virus glycoprotein B in complex with Fab fragments derived from human monoclonal antibody 93kCOMPLEXall0MULTIPLE SOURCES
2human monoclonal antibody 93k FabCOMPLEX#1-#21RECOMBINANT
3Varicella zoster virus glycoprotein BCOMPLEX#31NATURAL
Molecular weightValue: 0.75 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Human herpesvirus 3 (Varicella-zoster virus)10335
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 98 % / Chamber temperature: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 12 sec. / Electron dose: 7.5 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 4 / Num. of real images: 11283
EM imaging opticsEnergyfilter slit width: 20 eV
Image scansMovie frames/image: 60

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Processing

SoftwareName: PHENIX / Version: 1.15.2_3472: / Classification: refinement
EM software
IDNameCategory
2SerialEMimage acquisition
4CTFFINDCTF correction
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 856068 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00619980
ELECTRON MICROSCOPYf_angle_d0.6227141
ELECTRON MICROSCOPYf_dihedral_angle_d11.0611907
ELECTRON MICROSCOPYf_chiral_restr0.0473015
ELECTRON MICROSCOPYf_plane_restr0.0043480

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