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- EMDB-24073: Complex of Bet v 1 with the Fab fragments of a three antibody cocktail -

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Basic information

Entry
Database: EMDB / ID: EMD-24073
TitleComplex of Bet v 1 with the Fab fragments of a three antibody cocktail
Map data
Sample
  • Complex: Complex of Bet v 1 with the Fab fragments of a three antibody cocktail
    • Complex: Major pollen allergen
      • Protein or peptide: Major pollen allergen Bet v 1-A
    • Complex: antibody cocktail
      • Protein or peptide: REGN5713 antibody Fab fragment heavy chain
      • Protein or peptide: REGN5713 antibody Fab fragment light chain
      • Protein or peptide: REGN5715 antibody Fab fragment heavy chain
      • Protein or peptide: REGN5715 antibody Fab fragment light chain
      • Protein or peptide: REGN5714 antibody Fab fragment light chain
      • Protein or peptide: REGN5714 antibody Fab fragment heavy chain
Function / homology
Function and homology information


response to biotic stimulus / abscisic acid binding / abscisic acid-activated signaling pathway / protein phosphatase inhibitor activity / defense response / signaling receptor activity / cytoplasm
Similarity search - Function
Pathogenesis-related protein Bet v I family / Pathogenesis-related proteins Bet v I family signature. / Bet v I type allergen / Bet v I/Major latex protein / Pathogenesis-related protein Bet v 1 family / START-like domain superfamily
Similarity search - Domain/homology
Major pollen allergen Bet v 1-A
Similarity search - Component
Biological speciesBetula pendula (European white birch) / Homo sapiens (human) / European white birch, Betula verrucosa
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsRomero-Hernandez A / Franklin MC
CitationJournal: J Allergy Clin Immunol / Year: 2022
Title: Targeting immunodominant Bet v 1 epitopes with monoclonal antibodies prevents the birch allergic response.
Authors: Amanda Atanasio / Matthew C Franklin / Vishal Kamat / Annabel Romero Hernandez / Ashok Badithe / Li-Hong Ben / Jennifer Jones / Joannie Bautista / George D Yancopoulos / William Olson / ...Authors: Amanda Atanasio / Matthew C Franklin / Vishal Kamat / Annabel Romero Hernandez / Ashok Badithe / Li-Hong Ben / Jennifer Jones / Joannie Bautista / George D Yancopoulos / William Olson / Andrew J Murphy / Matthew A Sleeman / Jamie M Orengo
Abstract: BACKGROUND: Blocking the major cat allergen, Fel d 1, with mAbs was effective in preventing an acute cat allergic response.
OBJECTIVES: This study sought to extend the allergen-specific antibody approach and demonstrate that a combination of mAbs targeting Bet v 1, the immunodominant and most abundant allergenic protein ...OBJECTIVES: This study sought to extend the allergen-specific antibody approach and demonstrate that a combination of mAbs targeting Bet v 1, the immunodominant and most abundant allergenic protein in birch pollen, can prevent the birch allergic response.
METHODS: Bet v 1-specific mAbs, REGN5713, REGN5714, and REGN5715, were isolated using the VelocImmune platform. Surface plasmon resonance, x-ray crystallography, and cryo-electron microscopy ...METHODS: Bet v 1-specific mAbs, REGN5713, REGN5714, and REGN5715, were isolated using the VelocImmune platform. Surface plasmon resonance, x-ray crystallography, and cryo-electron microscopy determined binding kinetics and structural data. Inhibition of IgE-binding, basophil activation, and mast cell degranulation were assessed via blocking ELISA, flow cytometry, and the passive cutaneous anaphylaxis mouse model.
RESULTS: REGN5713, REGN5714, and REGN5715 bind with high affinity and noncompetitively to Bet v 1. A cocktail of all 3 antibodies, REGN5713/14/15, blocks IgE binding to Bet v 1 and inhibits Bet v 1- ...RESULTS: REGN5713, REGN5714, and REGN5715 bind with high affinity and noncompetitively to Bet v 1. A cocktail of all 3 antibodies, REGN5713/14/15, blocks IgE binding to Bet v 1 and inhibits Bet v 1- and birch pollen extract-induced basophil activation ex vivo and mast cell degranulation in vivo. Crystal structures of the complex of Bet v 1 with immunoglobulin antigen-binding fragments of REGN5713 or REGN5715 show distinct interaction sites on Bet v 1. Cryo-electron microscopy reveals a planar and roughly symmetrical complex formed by REGN5713/14/15 bound to Bet v 1.
CONCLUSIONS: These data confirm the immunodominance of Bet v 1 in birch allergy and demonstrate blockade of the birch allergic response with REGN5713/14/15. Structural analyses show simultaneous ...CONCLUSIONS: These data confirm the immunodominance of Bet v 1 in birch allergy and demonstrate blockade of the birch allergic response with REGN5713/14/15. Structural analyses show simultaneous binding of REGN5713, REGN5714, and REGN5715 with substantial areas of Bet v 1 exposed, suggesting that targeting specific epitopes is sufficient to block the allergic response.
History
DepositionMay 19, 2021-
Header (metadata) releaseJul 21, 2021-
Map releaseJul 21, 2021-
UpdateJan 19, 2022-
Current statusJan 19, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 5.7
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 5.7
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mxl
  • Surface level: 5.7
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24073.png

Downloads & links

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Map

FileDownload / File: emd_24073.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 5.7 / Movie #1: 5.7
Minimum - Maximum-14.240236 - 29.736195
Average (Standard dev.)-8.4271793e-13 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 228.79999 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z220220220
origin x/y/z0.0000.0000.000
length x/y/z228.800228.800228.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ220220220
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS220220220
D min/max/mean-14.24029.736-0.000

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Supplemental data

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Sample components

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Entire : Complex of Bet v 1 with the Fab fragments of a three antibody cocktail

EntireName: Complex of Bet v 1 with the Fab fragments of a three antibody cocktail
Components
  • Complex: Complex of Bet v 1 with the Fab fragments of a three antibody cocktail
    • Complex: Major pollen allergen
      • Protein or peptide: Major pollen allergen Bet v 1-A
    • Complex: antibody cocktail
      • Protein or peptide: REGN5713 antibody Fab fragment heavy chain
      • Protein or peptide: REGN5713 antibody Fab fragment light chain
      • Protein or peptide: REGN5715 antibody Fab fragment heavy chain
      • Protein or peptide: REGN5715 antibody Fab fragment light chain
      • Protein or peptide: REGN5714 antibody Fab fragment light chain
      • Protein or peptide: REGN5714 antibody Fab fragment heavy chain

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Supramolecule #1: Complex of Bet v 1 with the Fab fragments of a three antibody cocktail

SupramoleculeName: Complex of Bet v 1 with the Fab fragments of a three antibody cocktail
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Major pollen allergen

SupramoleculeName: Major pollen allergen / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Betula pendula (European white birch)

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Supramolecule #3: antibody cocktail

SupramoleculeName: antibody cocktail / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#2, #4-#7
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)

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Macromolecule #1: REGN5713 antibody Fab fragment heavy chain

MacromoleculeName: REGN5713 antibody Fab fragment heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.560197 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLQESGPG LVKPSETLSL TCSVSGGSIT NYFWTWIRQS PGKGLEWIGY IYYSGGTNYN PSLKSRVTIS IDTSKNQFSL NMNSVTAAD TAVYYCAGSY YYGVDVWGQG TTVTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF PEPVTVSWNS G ALTSGVHT ...String:
QVQLQESGPG LVKPSETLSL TCSVSGGSIT NYFWTWIRQS PGKGLEWIGY IYYSGGTNYN PSLKSRVTIS IDTSKNQFSL NMNSVTAAD TAVYYCAGSY YYGVDVWGQG TTVTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF PEPVTVSWNS G ALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTKTYT CNVDHKPSNT KVDKRVESKY GPP

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Macromolecule #2: REGN5713 antibody Fab fragment light chain

MacromoleculeName: REGN5713 antibody Fab fragment light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.534207 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EIVLTQSPAT LSLSPGERAT LSCRASQSIK SFLAWYRQKP GQAPRLLIYD ASNRPTGIPA RFSGSGSGTD FTLTINSLES EDFAVYFCQ QRNNWPFTFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
EIVLTQSPAT LSLSPGERAT LSCRASQSIK SFLAWYRQKP GQAPRLLIYD ASNRPTGIPA RFSGSGSGTD FTLTINSLES EDFAVYFCQ QRNNWPFTFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #3: Major pollen allergen Bet v 1-A

MacromoleculeName: Major pollen allergen Bet v 1-A / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: European white birch, Betula verrucosa
Molecular weightTheoretical: 17.592791 KDa
SequenceString:
MGVFNYETET TSVIPAARLF KAFILDGDNL FPKVAPQAIS SVENIEGNGG PGTIKKISFP EGFPFKYVKD RVDEVDHTNF KYNYSVIEG GPIGDTLEKI SNEIKIVATP DGGSILKISN KYHTKGDHEV KAEQVKASKE MGETLLRAVE SYLLAHSDAY N

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Macromolecule #4: REGN5715 antibody Fab fragment heavy chain

MacromoleculeName: REGN5715 antibody Fab fragment heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.322162 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVQSGAE VKKPGASVKV SCKASGYTFI SYNIFWVRQA TGQGLDWMGW MNPFRNNAGY AQKFQGRVTV TWDTSISTAY MELSSLSSE DTAIYYCARE HGSSWGFFDY WGQGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
QVQLVQSGAE VKKPGASVKV SCKASGYTFI SYNIFWVRQA TGQGLDWMGW MNPFRNNAGY AQKFQGRVTV TWDTSISTAY MELSSLSSE DTAIYYCARE HGSSWGFFDY WGQGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK PSNTKVDKRV ESKYGPP

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Macromolecule #5: REGN5715 antibody Fab fragment light chain

MacromoleculeName: REGN5715 antibody Fab fragment light chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.446953 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGSSPWTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGSSPWTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #6: REGN5714 antibody Fab fragment light chain

MacromoleculeName: REGN5714 antibody Fab fragment light chain / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.341904 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EIVMTQSPAT LSVSPGERAT LSCRASQSVS SSLAWYQQKP GQAPRRLIYS ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAIYYCH QYNNWPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
EIVMTQSPAT LSVSPGERAT LSCRASQSVS SSLAWYQQKP GQAPRRLIYS ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAIYYCH QYNNWPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #7: REGN5714 antibody Fab fragment heavy chain

MacromoleculeName: REGN5714 antibody Fab fragment heavy chain / type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.915615 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EVQLVESGGD LVQPGGSLRL SCAASGFTFS SYEMNWVRQA PGKGLEWVSF ISDSSSNIYY ADSVKGRFTI SRDNAKKSLY LQMTSLRAE DTAVYYCARE AIGSTSFDNW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS W NSGALTSG ...String:
EVQLVESGGD LVQPGGSLRL SCAASGFTFS SYEMNWVRQA PGKGLEWVSF ISDSSSNIYY ADSVKGRFTI SRDNAKKSLY LQMTSLRAE DTAVYYCARE AIGSTSFDNW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS W NSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTK TYTCNVDHKP SNTKVDKRVE SKYGPP

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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 / Instrument: FEI VITROBOT MARK IV

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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
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 44.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 149585

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