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- PDB-7mxl: Complex of Bet v 1 with the Fab fragments of a three antibody cocktail -

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Basic information

Entry
Database: PDB / ID: 7mxl
TitleComplex of Bet v 1 with the Fab fragments of a three antibody cocktail
Components
  • (REGN5713 antibody Fab fragment ...) x 2
  • (REGN5714 antibody Fab fragment ...) x 2
  • (REGN5715 antibody Fab fragment ...) x 2
  • Major pollen allergen Bet v 1-A
KeywordsALLERGEN / COMPLEX / ANTIBODY / BIRCH POLLEN ALLERGEN BET V 1
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 speciesHomo sapiens (human)
Betula pendula (European white birch)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsRomero-Hernandez, A. / Franklin, M.C.
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 21, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 19, 2022Group: Database references / Category: citation / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: REGN5713 antibody Fab fragment heavy chain
B: REGN5713 antibody Fab fragment light chain
C: Major pollen allergen Bet v 1-A
J: REGN5715 antibody Fab fragment heavy chain
K: REGN5715 antibody Fab fragment light chain
L: REGN5714 antibody Fab fragment light chain
H: REGN5714 antibody Fab fragment heavy chain


Theoretical massNumber of molelcules
Total (without water)159,7147
Polymers159,7147
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 1 molecules C

#3: Protein Major pollen allergen Bet v 1-A / Allergen Bet v I-A


Mass: 17592.791 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Betula pendula (European white birch) / References: UniProt: P15494

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Antibody , 6 types, 6 molecules ABJKLH

#1: Antibody REGN5713 antibody Fab fragment heavy chain


Mass: 23560.197 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody REGN5713 antibody Fab fragment light chain


Mass: 23534.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#4: Antibody REGN5715 antibody Fab fragment heavy chain


Mass: 24322.162 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#5: Antibody REGN5715 antibody Fab fragment light chain


Mass: 23446.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#6: Antibody REGN5714 antibody Fab fragment light chain


Mass: 23341.904 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#7: Antibody REGN5714 antibody Fab fragment heavy chain


Mass: 23915.615 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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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
1Complex of Bet v 1 with the Fab fragments of a three antibody cocktailCOMPLEXall0MULTIPLE SOURCES
2Major pollen allergenCOMPLEX#31NATURAL
3antibody cocktailCOMPLEX#1-#2, #4-#71RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
13Homo sapiens (human)9606
22Betula pendula (European white birch)3505
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 44 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
Image scansMovie frames/image: 30

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.1_4122refinement
PHENIX1.19.1_4122refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 149585 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 91.45 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003511122
ELECTRON MICROSCOPYf_angle_d0.584915126
ELECTRON MICROSCOPYf_chiral_restr0.04461700
ELECTRON MICROSCOPYf_plane_restr0.00481934
ELECTRON MICROSCOPYf_dihedral_angle_d4.74861527

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