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- PDB-9nq3: Crystal structure of SARS-CoV-2 S2 directed Fab 1871 -

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Basic information

Entry
Database: PDB / ID: 9nq3
TitleCrystal structure of SARS-CoV-2 S2 directed Fab 1871
Components
  • 1871 Fab heavy chain
  • 1871 Fab light chain
KeywordsIMMUNE SYSTEM / SARS-CoV-2 / ANTIBODY
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsMuthuraman, K. / Ivanochko, D. / 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 11, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 12, 2025Provider: repository / Type: Initial release
Revision 1.1May 27, 2026Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: 1871 Fab heavy chain
L: 1871 Fab light chain
A: 1871 Fab heavy chain
B: 1871 Fab light chain


Theoretical massNumber of molelcules
Total (without water)95,4674
Polymers95,4674
Non-polymers00
Water39622
1
H: 1871 Fab heavy chain
L: 1871 Fab light chain


Theoretical massNumber of molelcules
Total (without water)47,7332
Polymers47,7332
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: 1871 Fab heavy chain
B: 1871 Fab light chain


Theoretical massNumber of molelcules
Total (without water)47,7332
Polymers47,7332
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.192, 101.333, 134.982
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221
Space group name HallP22ab(y,z,x)
Symmetry operation#1: x,y,z
#2: x+1/2,-y,-z+1/2
#3: -x,y,-z
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
d_1ens_1(chain "A" and (resid 1 through 12 or (resid 13...
d_2ens_1(chain "H" and ((resid 1 and (name N or name...
d_1ens_2(chain "B" and (resid 1 through 189 or (resid 190...
d_2ens_2(chain "L" and (resid 1 through 144 or (resid 145...

NCS domain segments:

Component-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_1ens_1LYSLYSAC1 - 2261 - 226
d_2ens_1LYSLYSHA1 - 2261 - 226
d_1ens_2GLUGLUBD1 - 2151 - 215
d_2ens_2GLUGLULB1 - 2151 - 215

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(-0.999588309223, 0.0114390651896, -0.0263127317394), (0.0114754999593, 0.99993339274, -0.00123409220171), (0.0262968622593, -0.00153553588934, -0.999652998377)39.9971413592, -50.9446683183, -11.798229794
2given(-0.999405746851, 0.0169045138164, -0.0300398164844), (0.0171195346154, 0.999829536768, -0.0069151241262), (0.0299177989889, -0.00742528247006, -0.999524782326)39.390404539, -51.0875279528, -11.1196395355

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Components

#1: Antibody 1871 Fab heavy chain


Mass: 24054.006 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody 1871 Fab light chain


Mass: 23679.383 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.94 Å3/Da / Density % sol: 58.22 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 0.1 M sodium acetate, pH 4.6 and 3.5 M sodium formate

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1.033167 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Dec 7, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033167 Å / Relative weight: 1
ReflectionResolution: 2.5→70.2 Å / Num. obs: 47883 / % possible obs: 99.85 % / Redundancy: 7 % / CC1/2: 0.987 / Net I/σ(I): 6.14
Reflection shellResolution: 2.5→2.56 Å / Num. unique obs: 23530 / CC1/2: 0.785

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Processing

Software
NameVersionClassification
PHENIX1.21rc1_5127refinement
XPREPdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→70.2 Å / SU ML: 0.3414 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 28.2138
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2513 1998 5.04 %
Rwork0.2156 37681 -
obs0.2174 39679 99.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.74 Å2
Refinement stepCycle: LAST / Resolution: 2.5→70.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6622 0 0 22 6644
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00446778
X-RAY DIFFRACTIONf_angle_d0.85759236
X-RAY DIFFRACTIONf_chiral_restr0.05251042
X-RAY DIFFRACTIONf_plane_restr0.00711186
X-RAY DIFFRACTIONf_dihedral_angle_d14.35442390
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2CAX-RAY DIFFRACTIONTorsion NCS0.55293819078
ens_2d_2DBX-RAY DIFFRACTIONTorsion NCS0.531550235269
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.560.32761410.28912648X-RAY DIFFRACTION99.61
2.56-2.630.3021390.28212617X-RAY DIFFRACTION99.82
2.63-2.710.32421410.28492661X-RAY DIFFRACTION99.72
2.71-2.80.33371420.27692660X-RAY DIFFRACTION99.89
2.8-2.90.34741410.28232664X-RAY DIFFRACTION99.93
2.9-3.010.28961400.2772648X-RAY DIFFRACTION99.89
3.01-3.150.36181410.27212671X-RAY DIFFRACTION99.75
3.15-3.320.30511420.25072684X-RAY DIFFRACTION100
3.32-3.520.25581430.21942696X-RAY DIFFRACTION100
3.52-3.80.22561410.20082678X-RAY DIFFRACTION99.89
3.8-4.180.2091430.18182696X-RAY DIFFRACTION99.89
4.18-4.780.18371450.14872717X-RAY DIFFRACTION99.97
4.78-6.020.19731450.16032761X-RAY DIFFRACTION99.93
6.02-70.20.20191540.1922880X-RAY DIFFRACTION99.61
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)
1-0.8280584302880.3428170662090.07256597148320.570566387515-0.9177834615323.339889439530.114204301490.1566676687890.08156881998160.1084938927550.2441553689610.240766616275-0.471617720803-1.2842066541-0.2585035091830.284230248170.1821648934120.06915216127940.6861555499110.1079250509180.38001750696713.47991968957.4848154794-7.08857507465
20.6862956660520.233586966185-0.7101221692730.547137391314-0.5903236557583.026876697760.06921235247180.094922539233-0.00182848904314-0.09578464938-0.03728804136610.04714140398930.0369254168541-0.254967074492-0.04443913396270.1853605172690.0416408395281-0.01228494356240.221746009454-0.008963288902220.21794075697330.373148445853.1912706043-8.62108837018
30.0666850721402-0.18147591953-0.2108987333220.7643292552070.6484183669233.925666891590.047171949557-0.0992673485061-0.129060861706-0.08294087721560.0950286831188-0.256878272522-0.07831448702770.70685775282-0.158529204590.226645980725-0.01940552701760.02648917630750.380870011528-0.06092686326760.43038165104227.8729626195108.223861475-4.191382783
40.829514767113-0.268440914184-0.6112745611091.742160584271.160791427472.662180259580.0911784856248-0.0459017962492-0.04920109683290.0531906065477-0.0714612308061-0.07838997387590.1212692464870.249407328154-0.01829532124430.2197276823880.00579467251402-0.0203875923460.2009114333170.02364689247030.27671679120810.8818081761104.219386741-2.83811422021
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'H' and resid 1 through 226)HA1 - 2261 - 226
22(chain 'L' and resid 1 through 215)LB1 - 2151 - 215
33(chain 'A' and resid 1 through 226)AC1 - 2261 - 226
44(chain 'B' and resid 1 through 215)BD1 - 2151 - 215

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