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- EMDB-45444: Dissecting human monoclonal antibody responses from mRNA and prot... -

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Entry
Database: EMDB / ID: EMD-45444
TitleDissecting human monoclonal antibody responses from mRNA and protein-based booster vaccinations against XBB1.5 SARS-CoV-2
Map dataSharpened map using DeepEMhancer
Sample
  • Complex: M2 Fab complexed with NTD on XBB1.5 Spike
    • Protein or peptide: M2 Fab Heavy Chain
    • Protein or peptide: M2 Fab Light Chain
    • Protein or peptide: Spike glycoprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsSARS-CoV-2 / Antibody / NTD / IMMUNE SYSTEM / VIRUS LIKE PARTICLE / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell ...Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell / membrane fusion / Attachment and Entry / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / receptor ligand activity / endocytosis involved in viral entry into host cell / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / identical protein binding / membrane / plasma membrane
Similarity search - Function
Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Spike glycoprotein S2, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / Severe acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 2.37 Å
AuthorsBajic G / Civljak A
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI168178 United States
CitationJournal: bioRxiv / Year: 2024
Title: Dissecting human monoclonal antibody responses from mRNA- and protein-based XBB.1.5 COVID-19 monovalent vaccines.
Authors: Raianna F Fantin / Jordan J Clark / Hallie Cohn / Deepika Jaiswal / Bailey Bozarth / Alesandro Civljak / Vishal Rao / Igor Lobo / Jessica R Nardulli / Komal Srivastava / Jeremy Yong / Robert ...Authors: Raianna F Fantin / Jordan J Clark / Hallie Cohn / Deepika Jaiswal / Bailey Bozarth / Alesandro Civljak / Vishal Rao / Igor Lobo / Jessica R Nardulli / Komal Srivastava / Jeremy Yong / Robert Andreata-Santos / Kaitlyn Bushfield / Edward S Lee / Gagandeep Singh / / Steven H Kleinstein / Florian Krammer / Viviana Simon / Goran Bajic / Camila H Coelho /
Abstract: The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines ...The emergence of highly contagious and immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has required reformulation of coronavirus disease 2019 (COVID-19) vaccines to target those new variants specifically. While previous infections and booster vaccinations can enhance variant neutralization, it is unclear whether the monovalent version, administered using either mRNA or protein-based vaccine platforms, can elicit B-cell responses specific for Omicron XBB.1.5 variants. Here, we dissected the genetic antibody repertoire of 603 individual plasmablasts derived from five individuals who received a monovalent XBB.1.5 vaccination either with mRNA (Moderna or Pfizer/BioNtech) or adjuvanted protein (Novavax). From these sequences, we expressed 100 human monoclonal antibodies and determined binding, affinity and protective potential against several SARS-CoV-2 variants, including JN.1. We then select two vaccine-induced XBB.1.5 mAbs, M2 and M39. M2 mAb was a , antibody, i.e., specific for XBB.1.5 but not ancestral SARS-CoV-2. M39 bound and neutralized both XBB.1.5 and JN.1 strains. Our high-resolution cryo-electron microscopy (EM) structures of M2 and M39 in complex with the XBB.1.5 spike glycoprotein defined the epitopes engaged and revealed the molecular determinants for the mAbs' specificity. These data show, at the molecular level, that monovalent, variant-specific vaccines can elicit functional antibodies, and shed light on potential functional and genetic differences of mAbs induced by vaccinations with different vaccine platforms.\.
History
DepositionJun 21, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45444.png

Downloads & links

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Map

FileDownload / File: emd_45444.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map using DeepEMhancer
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 512 pix.
= 422.4 Å		0.83 Å/pix.
x 512 pix.
= 422.4 Å		0.83 Å/pix.
x 512 pix.
= 422.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0016688058 - 1.8286128
Average (Standard dev.)0.00032979023 (±0.010310783)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 422.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_45444_msk_1.map
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Additional map: Global map

Fileemd_45444_additional_1.map
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Additional map: Local sharp map

Fileemd_45444_additional_2.map
AnnotationLocal sharp map
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Additional map: Local map

Fileemd_45444_additional_3.map
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Additional map: Global half map 1

Fileemd_45444_additional_4.map
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Additional map: Global half map 2

Fileemd_45444_additional_5.map
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Additional map: Global sharp map

Fileemd_45444_additional_6.map
AnnotationGlobal sharp map
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Half map: Local half map 1

Fileemd_45444_half_map_1.map
AnnotationLocal half map 1
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Half map: Local half map 2

Fileemd_45444_half_map_2.map
AnnotationLocal half map 2
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Sample components

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Entire : M2 Fab complexed with NTD on XBB1.5 Spike

EntireName: M2 Fab complexed with NTD on XBB1.5 Spike
Components
  • Complex: M2 Fab complexed with NTD on XBB1.5 Spike
    • Protein or peptide: M2 Fab Heavy Chain
    • Protein or peptide: M2 Fab Light Chain
    • Protein or peptide: Spike glycoprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: M2 Fab complexed with NTD on XBB1.5 Spike

SupramoleculeName: M2 Fab complexed with NTD on XBB1.5 Spike / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Macromolecule #1: M2 Fab Heavy Chain

MacromoleculeName: M2 Fab Heavy Chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.723674 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QLQESGPGLV KPSEILSLTC SVSGGSINTN MYYWGWIRQP PGKGLEWIGS IYYSGTTYYN PSLKSRVTMS VDTSENQFSL KLTSVTAAD TSVYFCARLP LGERIDYWGR GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN S GALTSGVH ...String:
QLQESGPGLV KPSEILSLTC SVSGGSINTN MYYWGWIRQP PGKGLEWIGS IYYSGTTYYN PSLKSRVTMS VDTSENQFSL KLTSVTAAD TSVYFCARLP LGERIDYWGR GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN S GALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDK

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Macromolecule #2: M2 Fab Light Chain

MacromoleculeName: M2 Fab Light Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.565842 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SSDLTQPPSV SVSPGQTASI TCSGNKLGDT YVFWYQQKPG QSPVAVINED NKRPSGIPER FSGSNSGNTA TLTISGTQTM DEADYYCQV WDSSQMVFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS ...String:
SSDLTQPPSV SVSPGQTASI TCSGNKLGDT YVFWYQQKPG QSPVAVINED NKRPSGIPER FSGSNSGNTA TLTISGTQTM DEADYYCQV WDSSQMVFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS

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Macromolecule #3: Spike glycoprotein

MacromoleculeName: Spike glycoprotein / type: protein_or_peptide / ID: 3 / Details: variant XBB1.5 on a hexapro background / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 136.398297 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: (PCA)CVNLITRTQ SYTNSFTRGV YYPDKVFRSS VLHSTQDLFL PFFSNVTWFH AIHVSGTNGT KRFDNPALPF NDGVYF AST EKSNIIRGWI FGTTLDSKTQ SLLIVNNATN VVIKVCEFQF CNDPFLDVYQ KNNKSWMESE FRVYSSANNC TFEYVSQ PF LMDLEGKEGN ...String:
(PCA)CVNLITRTQ SYTNSFTRGV YYPDKVFRSS VLHSTQDLFL PFFSNVTWFH AIHVSGTNGT KRFDNPALPF NDGVYF AST EKSNIIRGWI FGTTLDSKTQ SLLIVNNATN VVIKVCEFQF CNDPFLDVYQ KNNKSWMESE FRVYSSANNC TFEYVSQ PF LMDLEGKEGN FKNLREFVFK NIDGYFKIYS KHTPINLERD LPQGFSALEP LVDLPIGINI TRFQTLLALH RSYLTPVD S SSGWTAGAAA YYVGYLQPRT FLLKYNENGT ITDAVDCALD PLSETKCTLK SFIVEKGIYQ TSNFRVQPTE SIVRFPNIT NLCPFHEVFN ATTFASVYAW NRKRISNCVA DYSVIYNFAP FFAFKCYGVS PTKLNDLCFT NVYADSFVIR GNEVSQIAPG QTGNIADYN YKLPDDFTGC VIAWNSNKLD SKPSGNYNYL YRFLRKSKLK PFERDISTEI YQVGNKPCNG VAGPNCYSPL Q SYGFRPTY GVGHQPYRVV VLSFELLHAP ATVCGPKKST NLVKNKCVNF NFNGLTGTGV LTESNKKFLP FQQFGRDIAD TT DAVRDPQ TLEILDITPC SFGGVSVITP GTNTSNQVAV LYQGVNCTEV PVAIHADQLT PTWRVYSTGS NVFQTRAGCL IGA EYVNNS YECDIPIGAG ICASYQTQTK SHGSASSVAS QSIIAYTMSL GAENSVAYSN NSIAIPTNFT ISVTTEILPV SMTK TSVDC TMYICGDSTE CSNLLLQYGS FCTQLKRALT GIAVEQDKNT QEVFAQVKQI YKTPPIKYFG GFNFSQILPD PSKPS KRSP IEDLLFNKVT LADAGFIKQY GDCLGDIAAR DLICAQKFNG LTVLPPLLTD EMIAQYTSAL LAGTITSGWT FGAGPA LQI PFPMQMAYRF NGIGVTQNVL YENQKLIANQ FNSAIGKIQD SLSSTPSALG KLQDVVNHNA QALNTLVKQL SSKFGAI SS VLNDILSRLD PPEAEVQIDR LITGRLQSLQ TYVTQQLIRA AEIRASANLA ATKMSECVLG QSKRVDFCGK GYHLMSFP Q SAPHGVVFLH VTYVPAQEKN FTTAPAICHD GKAHFPREGV FVSNGTHWFV TQRNFYEPQI ITTDNTFVSG NCDVVIGIV NNTVYDPLQP ELDSFKEELD KYFKNHTSPD VDLGDISGIN ASVVNIQKEI DRLNEVAKNL NESLIDLQEL GKYEQGSGYI PEAPRDGQA YVRKDGEWVL LSTFLGRSLE VLFQ

UniProtKB: Spike glycoprotein

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration2 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.883 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.37 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 298206
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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