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- PDB-9nqz: cryo-EM structure of broad betacoronavirus binding antibody 1871 ... -

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Basic information

Entry
Database: PDB / ID: 9nqz
Titlecryo-EM structure of broad betacoronavirus binding antibody 1871 in complex with OC43 S2 subunit
Components
  • 1871 Fab heavy chain
  • 1871 Fab light chain
  • Spike glycoprotein
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / OC43 / Betacoronavirus / antibody / viral glycoprotein / IMMUNE SYSTEM-VIRAL PROTEIN complex / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated virion attachment to host cell / 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 / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Spike (S) protein S1 subunit, receptor-binding domain, HCoV-OC43-like / Spike (S) protein S1 subunit, N-terminal domain, murine hepatitis virus-like / Spike glycoprotein S2, coronavirus, C-terminal / Coronavirus spike glycoprotein S2, intravirion / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. ...Spike (S) protein S1 subunit, receptor-binding domain, HCoV-OC43-like / Spike (S) protein S1 subunit, N-terminal domain, murine hepatitis virus-like / Spike glycoprotein S2, coronavirus, C-terminal / Coronavirus spike glycoprotein S2, intravirion / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / 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 / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Spike glycoprotein S2 superfamily, coronavirus / 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, coronavirus / Coronavirus spike glycoprotein S2
Similarity search - Domain/homology
Biological speciesHuman coronavirus OC43
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsMuthuraman, K. / Jackman, M.J. / Julien, J.P.
Funding support United States, 1items
OrganizationGrant numberCountry
Bill & Melinda Gates FoundationINV-023398 United States
CitationJournal: J Virol / Year: 2025
Title: Human antibody targeting of coronavirus spike S2 subunit is associated with protection mediated by Fc effector functions.
Authors: Krithika Muthuraman / Matthew Jackman / Yu Liang / Meghan E Garrett / Hong Cui / Loan Vu Hong Nguyen / Danton Ivanochko / Chengjin Ye / Paula A Pino / Amberlee Hicks / Billie Maingot / Erik ...Authors: Krithika Muthuraman / Matthew Jackman / Yu Liang / Meghan E Garrett / Hong Cui / Loan Vu Hong Nguyen / Danton Ivanochko / Chengjin Ye / Paula A Pino / Amberlee Hicks / Billie Maingot / Erik Yusko / Sharon Benzeno / Luis Martínez-Sobrido / Jordi B Torrelles / Amy E Gilbert / Benjamin Evan Russell Rubin / Gladys Keitany / Arif Jetha / Jean-Philippe Julien /
Abstract: Over the past two decades, betacoronaviruses (β-CoVs) have caused two epidemics and a pandemic and remain a high risk for future outbreaks through zoonotic transmissions, highlighting the need for ...Over the past two decades, betacoronaviruses (β-CoVs) have caused two epidemics and a pandemic and remain a high risk for future outbreaks through zoonotic transmissions, highlighting the need for broad biomedical countermeasures. Here, we describe a convalescent human monoclonal antibody (mAb 1871) that targets the S2 subunit of the coronavirus spike protein, with broad β-CoVs binding and sarbecovirus neutralization. Cryo-electron microscopy analysis revealed that mAb 1871 binds the upstream helix of the S2 subunit, interacting with partially conserved residues, providing a molecular basis for its cross-reactivity. Though less potent than receptor-binding domain-directed antibodies-approximately 500-fold lower neutralization potency than the emergency use authorized receptor-binding domain (RBD)-directed Pemgarda mAb against wild-type SARS-CoV-2-mAb 1871 provides protective efficacy in a mouse model. Notably, Fc effector functions are critical for its protection. This study further highlights the Fc dependence of S2-directed antibodies for protection and identifies a conserved epitope in the S2 subunit as a potential target of broad-β-CoVs countermeasures.IMPORTANCEBats and pangolins are natural reservoirs of betacoronaviruses (β-CoVs) and continue to pose a significant risk for future outbreaks through zoonotic transmissions. This highlights the need for effective countermeasures to prevent future pandemics. While neutralizing antibodies targeting the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) received emergency use authorization, many have lost efficacy as the virus evolved, and authorizations have been revoked. In contrast to the S1 subunit, the spike protein S2 subunit is more conserved across β-CoVs, making it an attractive target for the development of broadly neutralizing antibodies. Here, we describe a human mAb that targets a conserved epitope in the S2 subunit, demonstrating broad β-CoV binding, sarbecovirus neutralization, and protection mediated by Fc effector functions in a mouse model. These findings have important implications for pan-β-CoVs therapeutics and vaccine development.
History
DepositionMar 13, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 12, 2025Provider: repository / Type: Initial release
Revision 1.0Nov 12, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 12, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Nov 12, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Nov 12, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1Dec 3, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Dec 3, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Spike glycoprotein
B: Spike glycoprotein
C: Spike glycoprotein
D: 1871 Fab light chain
E: 1871 Fab heavy chain
F: 1871 Fab light chain
G: 1871 Fab heavy chain
H: 1871 Fab heavy chain
L: 1871 Fab light chain


Theoretical massNumber of molelcules
Total (without water)269,3669
Polymers269,3669
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Spike glycoprotein / S glycoprotein / E2 / Peplomer protein


Mass: 64176.945 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human coronavirus OC43 / Production host: Homo sapiens (human) / References: UniProt: A0A0B4N716
#2: Antibody 1871 Fab light chain


Mass: 12022.502 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody 1871 Fab heavy chain


Mass: 13589.204 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
Has protein modificationY

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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
IDNameTypeDetailsEntity IDParent-IDSource
1OC43 S2 subunit complex with Fab 1871COMPLEXOC43 spike protein S2 subunit trimer, Fab fragment generated by recombinant expressionall0MULTIPLE SOURCES
2OC43 S2 subunitCOMPLEX#11RECOMBINANT
3Fab 1871COMPLEX#2-#31RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.34 MDaNO
210.05 MDaYES
310.05 MDaYES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Human coronavirus OC4331631
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenConc.: 0.25 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: The sample was monodisperse
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in.
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 54 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 2 / Num. of real images: 4795

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Processing

EM softwareName: PHENIX / Version: 1.21rc1_5127 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 109156 / Details: Non-uniform refinement job in CryoSPARC. / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 42.43 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005412243
ELECTRON MICROSCOPYf_angle_d0.548816635
ELECTRON MICROSCOPYf_chiral_restr0.0451848
ELECTRON MICROSCOPYf_plane_restr0.00422151
ELECTRON MICROSCOPYf_dihedral_angle_d14.65994395

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