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- PDB-7uhz: Post-fusion ectodomain of HSV-1 gB in complex with BMPC-23 Fab -

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Basic information

Entry
Database: PDB / ID: 7uhz
TitlePost-fusion ectodomain of HSV-1 gB in complex with BMPC-23 Fab
Components
  • BMPC-23 Fab Heavy chain
  • BMPC-23 Fab Light chain
  • Envelope glycoprotein B
KeywordsVIRAL PROTEIN / glycoprotein / fusogen / antibody / ADCC
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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsWindsor, I.W. / Kong, S.L. / Garforth, S.J. / Almo, S.C. / Harrison, S.C.
Funding support United States, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.year / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: BMPC-23 Fab Heavy chain
I: BMPC-23 Fab Heavy chain
J: BMPC-23 Fab Heavy chain
L: BMPC-23 Fab Light chain
M: BMPC-23 Fab Light chain
N: BMPC-23 Fab Light chain
A: Envelope glycoprotein B
B: Envelope glycoprotein B
C: Envelope glycoprotein B


Theoretical massNumber of molelcules
Total (without water)291,4999
Polymers291,4999
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Antibody BMPC-23 Fab Heavy chain


Mass: 13425.734 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#2: Antibody BMPC-23 Fab Light chain


Mass: 12072.557 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Protein Envelope glycoprotein B / gB


Mass: 71668.188 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human alphaherpesvirus 1 strain KOS / Strain: KOS / Gene: gB, UL27 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P06437

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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

ComponentName: Trimeric HSV-1 gB in complex with three BCMP-23 Fabs / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 FIELDBright-field microscopy / Nominal defocus max: 1800 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 55.8 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 218056 / Symmetry type: POINT

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