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- PDB-7n0v: Complex of recombinant Bet v 1 with Fab fragment of REGN5715 -

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Basic information

Entry
Database: PDB / ID: 7n0v
TitleComplex of recombinant Bet v 1 with Fab fragment of REGN5715
Components
  • Major pollen allergen Bet v 1-A
  • REGN5715 Fab heavy chain
  • REGN5715 Fab light chain
KeywordsALLERGEN / Birch pollen / allergy / neutralizing antibody / immunotherapy
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 speciesMus musculus (house mouse)
Betula pendula (European white birch)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.71 Å
AuthorsFranklin, M.C. / Romero Hernandez, A.
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 26, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 11, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 19, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
H: REGN5715 Fab heavy chain
L: REGN5715 Fab light chain
C: Major pollen allergen Bet v 1-A


Theoretical massNumber of molelcules
Total (without water)68,5123
Polymers68,5123
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)133.105, 133.105, 145.420
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Space group name HallP612(x,y,z+5/12)

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Components

#1: Antibody REGN5715 Fab heavy chain


Mass: 24322.162 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody REGN5715 Fab light chain


Mass: 23446.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein Major pollen allergen Bet v 1-A / Allergen Bet v I-A


Mass: 20743.148 Da / Num. of mol.: 1 / Mutation: F63L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Betula pendula (European white birch) / Gene: BETVIA, BETVI / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P15494

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.71 Å3/Da / Density % sol: 54.68 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: PEG3350, PEG 400, Mg acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 3, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.7→100 Å / Num. obs: 8574 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 68.1 % / Biso Wilson estimate: 34.65 Å2 / Rmerge(I) obs: 0.302 / Rpim(I) all: 0.037 / Rrim(I) all: 0.305 / Χ2: 1.014 / Net I/σ(I): 23
Reflection shellResolution: 3.7→3.76 Å / Rmerge(I) obs: 2.68 / Mean I/σ(I) obs: 2 / Num. unique obs: 404 / CC1/2: 0.674 / Rpim(I) all: 0.384 / Rrim(I) all: 2.706 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1BV1 plus in-house Fab models

1bv1


Resolution: 3.71→49.09 Å / SU ML: 0.4684 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 35.6328
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3777 380 4.68 %
Rwork0.3268 7731 -
obs0.3294 8111 94.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 61.6 Å2
Refinement stepCycle: LAST / Resolution: 3.71→49.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4483 0 0 0 4483
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00194588
X-RAY DIFFRACTIONf_angle_d0.61516232
X-RAY DIFFRACTIONf_chiral_restr0.0435692
X-RAY DIFFRACTIONf_plane_restr0.0044800
X-RAY DIFFRACTIONf_dihedral_angle_d5.7248625
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.71-4.240.39321040.35922223X-RAY DIFFRACTION84.43
4.24-5.340.39211450.31392667X-RAY DIFFRACTION99.96
5.34-49.090.35321310.31592841X-RAY DIFFRACTION99.97
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.0009496085718330.01223126285190.005676306467570.02554624094030.01597398840760.0231327274617-0.1055360361480.0211578501697-0.0118078805406-0.00918364101595-0.122920768550.00435373801647-0.07811253684230.0277690216714-0.0550242888770.297783790221-0.047744426911-0.91590530471-0.00340540247775-0.6474085812950.0252178936279-32.674595574722.0701411861-31.1873529125
20.0177209892263-0.0150555891940.00714059946680.00954543102629-0.00126558890220.001112220949670.02481157396670.0102541403795-0.00885824563004-0.0211467321632-0.0435252217202-0.01696159573070.0121831025930.0519415855416-0.000673891220260.0706444986940.133769348687-0.1033881326020.3023380540790.09115902223010.326079889264-21.860481511422.5449814498-36.2114353761
30.006041147183920.05625148496720.02243563215340.2543684731590.05913569256460.0145681444984-0.00665399737410.03818836090350.06247660819850.0520951269997-0.0563287329659-0.0394749313305-0.06430198636670.02003801777030.02840945310680.1850743811780.336996666916-0.40217125295-0.122622503172-0.1627330159740.116545750689-27.056674056119.4268932068-27.5067092724
4-0.00916007079466-0.0390432911475-0.02272262358790.007189086661080.00158119817956-0.01702104320.195093474966-0.08078866103730.1561795422770.1098278371560.3807793197890.1043504596330.0644142735613-0.2740821055680.391456877628-0.04568635262770.0757165634805-0.583030199956-0.277407934872-0.873971300864-0.30208281463-44.485530681835.7212612111-12.2125545862
5-0.000122609070223-0.001239395520060.003138510835790.00239229671420.006372119442010.00425895354246-0.03152845289730.01334524949880.0104359371263-0.0166771625719-0.02049393046280.0252231121579-0.09424202904810.002059214422366.67168348293E-60.323928454253-0.0865954275797-0.1503702217560.194862029169-0.0475732219840.25894601982-41.29607436946.460094258-39.2463824793
60.003959517038770.0270390822747-0.007451237330250.04166726650350.01365179995530.0519092049075-0.06316497637020.008741689658150.0369925991336-0.0246020274151-0.1340694067480.002513908393110.01361238201330.0198010491427-0.1256990728980.26813426291-0.178873962143-0.349163148732-0.195579854561-0.225795237519-0.0463785900967-35.792001285839.507452723-45.4434314324
7-0.001282202589310.001740430363520.01228541212710.00303182972352-0.004989983347870.02786986335690.02004522693820.00845573079750.015928202013-0.04353708274410.03153708241290.03922949642370.01239219418310.003218499347440.0226505006570.171047559918-0.2404111825-0.3261133924630.00759852553461-0.2377968657110.129429964002-46.254027897232.8132519906-42.4513249121
8-0.006070782889870.00665911502098-0.01699217204750.00478424347947-0.00236539200406-0.007850351307820.13171830237-0.01604823822730.04139003447080.000803635482423-0.1070328987840.04118067202230.04298474141260.001475110846970.08847612224860.406967950188-0.0943913492922-0.447234797104-0.433403369504-0.3327811385470.262739804752-42.640883694142.0493996267-39.4719880828
9-0.00413927454371-0.01086645964540.00275577161113-0.0001484527794020.007704988413510.0007573356594640.0349825876868-0.0684489981274-0.04457353923080.0323614599937-0.016676896183-0.001068949985640.01146219537390.00192373515843-0.007897520399430.05256199042630.1906817065660.02322302042280.0376923818077-0.5932567975030.149678175787-43.457667083249.36528024751.68470217218
100.0515395066462-0.02041362653180.01333284548360.02930936751960.01703611379170.01254425928560.007420808775960.04522671994870.02444158156540.0236660568918-0.00785649302052-0.0146438190302-0.03053209592550.06039277781220.00690899120764-0.02158629537270.3160884962490.0646632658646-0.0338941112445-0.5911502210460.199723225484-40.141923069254.5401850855-11.5907153198
110.01281546553390.001189591985290.001841913605630.00114471870590.0004068313340130.0003931214151530.00455514276918-0.00904685109305-0.0182671899698-0.008009372318190.007892584615540.006392737005030.007043497125550.002288092633550.009855187253070.1419524230230.00560939857731-0.361302955941-0.0609562805063-0.08271793156270.186134273939-52.570956387846.4250449595-21.9069959184
120.0133950597446-0.01059068597190.00714750569956-0.001312572597280.002227377728060.000695113072559-0.018075522207-0.01530067797320.00381370788780.0361174503874-0.0711386689188-0.0382855272248-0.01524838461180.0216880972257-0.03954799158040.1683591470750.10102430997-0.207986532665-0.00463457913907-0.8071879478360.174131132035-37.547141434355.9212345115-2.72295035594
13-0.00320757220628-0.00385370937778-0.002090328168830.006304547094480.002154234946370.000754957980596-0.00425559633685-0.03951159726920.004674360166820.0140740279787-0.0115242364608-0.02169789603150.001658466818690.00349594253804-0.005755212350270.2260585620190.2824154216130.07931698896550.0773028594611-0.2842957070020.270230667612-45.397140846161.8824683051-5.47580128238
140.000697655004445-0.00180874513772-0.002505491813610.004559012315370.007153791203480.00502490243519-0.03827895194633.48814047517E-5-0.00408411959084-0.0316278161613-0.0490925485722-0.0353917950350.01603555589790.0307974473114-1.05633807886E-50.6765666230790.191104882765-0.01203715528380.544568446946-0.4132644752590.334258638256-31.38813589432.0019992951-70.3893124949
150.000530478663227-0.000359599420422-0.0005301067743340.000226471241494-0.0005051344215680.000951708774217-0.003470049390450.0100445442967-0.000883534577177-0.007364428016860.002169432347660.000815641125428-0.00767848272445-0.0072353136024-2.54098429366E-61.038251348790.1296083590580.07053788363821.155101367850.005381921643661.08291416502-16.92099787455.93454645666-57.404823735
160.036977178079-0.0025025509418-0.007041665825650.001512206313630.005310201753450.0273725526892-0.1118939808750.07248916047160.0871453648797-0.0048293407326-0.135642017354-0.0457814862685-0.002976650616660.0707431611377-0.1059793448210.4278610242150.1565403915780.1432913938280.356647467186-0.5150418608440.0409473947275-26.944704862619.1198539992-57.707649623
170.004065855599970.00035959091398-0.001375200799082.08760265241E-5-6.65366461537E-50.000425985158834-0.0009008630850190.002124256135910.00352530048404-0.00796268445415-0.00396633952060.004444889002480.0002648657516170.00046110081835-4.57062970624E-51.084893600320.0226923597102-0.04820359718811.106166704410.01238369097411.0193113039-30.019312139625.4813557649-70.8428632151
180.00207957010542-0.00335944611159-0.0003113710116410.03467397657690.01305136544840.0260553758408-0.00903279511668-0.033905668792-0.0354594267524-0.0159325698898-0.0156306754060.0381430203347-0.05049861964740.0580013713521-0.03273828477981.115967533070.469353886152-0.07719419857550.644516160516-1.05376996543-0.0406979640914-34.01635385237.5474092689-63.8637717753
190.00334515224437-0.00204092759667-0.00425084776325-0.002073283064060.006285602829710.0042777189109-0.00919609230019-0.01557600845650.002309196598550.00517315702469-0.020240690981-0.0774568342998-0.0117774985970.0301952120149-1.24045192221E-61.114990973770.154742133822-0.009836999256491.32813811091-0.129457122131.12953957418-18.778070319211.8081391624-66.0451550316
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'H' and (resid 1 through 52 )HA1 - 521 - 52
22chain 'H' and (resid 53 through 67 )HA53 - 6753 - 67
33chain 'H' and (resid 68 through 91 )HA68 - 9168 - 91
44chain 'H' and (resid 92 through 219 )HA92 - 21992 - 210
55chain 'L' and (resid 1 through 18 )LB1 - 181 - 18
66chain 'L' and (resid 19 through 39 )LB19 - 3919 - 39
77chain 'L' and (resid 40 through 62 )LB40 - 6240 - 62
88chain 'L' and (resid 63 through 114 )LB63 - 11463 - 114
99chain 'L' and (resid 115 through 129 )LB115 - 129115 - 129
1010chain 'L' and (resid 130 through 164 )LB130 - 164130 - 164
1111chain 'L' and (resid 165 through 175 )LB165 - 175165 - 175
1212chain 'L' and (resid 176 through 199 )LB176 - 199176 - 199
1313chain 'L' and (resid 200 through 215 )LB200 - 215200 - 215
1414chain 'C' and (resid 1 through 11 )CC1 - 111 - 11
1515chain 'C' and (resid 12 through 22 )CC12 - 2212 - 22
1616chain 'C' and (resid 23 through 57 )CC23 - 5723 - 57
1717chain 'C' and (resid 58 through 65 )CC58 - 6558 - 65
1818chain 'C' and (resid 66 through 129 )CC66 - 12966 - 129
1919chain 'C' and (resid 130 through 159 )CC130 - 159130 - 159

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