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- PDB-9ecy: Crystal structure of the SARS-CoV-2 NTD-targeted neutralizing ant... -

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Basic information

Entry
Database: PDB / ID: 9ecy
TitleCrystal structure of the SARS-CoV-2 NTD-targeted neutralizing antibody WRAIR-2039
Components
  • WRAIR-2039 Fab heavy chain
  • WRAIR-2039 Fab light chain
KeywordsIMMUNE SYSTEM / antibody / human antibody / neutralizing antibody / SARS-CoV-2
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.54 Å
AuthorsSankhala, R.S. / Jensen, J.L. / Joyce, M.G.
Funding support United States, 1items
OrganizationGrant numberCountry
Department of Defense (DOD, United States)W81XWH-18-2-0040 United States
CitationJournal: mBio / Year: 2025
Title: First-generation N-terminal domain supersite public antibodies retain activity against Omicron-derived lineages and protect mice against Omicron BA.5 challenge.
Authors: Vincent Dussupt / Jaime L Jensen / Paul V Thomas / Letzibeth Mendez-Rivera / Kerri G Lal / Michelle Zemil McCrea / Isabella Swafford / Joana Hernandez / Rajeshwer S Sankhala / Mekhala Rao / ...Authors: Vincent Dussupt / Jaime L Jensen / Paul V Thomas / Letzibeth Mendez-Rivera / Kerri G Lal / Michelle Zemil McCrea / Isabella Swafford / Joana Hernandez / Rajeshwer S Sankhala / Mekhala Rao / Juhi Arora / Agnes Hajduczki / Ningbo Jian / Phyllis A Rees / Indica Showell-De Leon / Gabriel Smith / Lauren Smith / Diana Wasson / Annika Schmid / I-Ting Teng / Tongqing Zhou / Peter D Kwong / Jeffrey R Currier / William W Reiley / Dominic Paquin-Proulx / Victoria R Polonis / Natalie D Collins / Nelson L Michael / M Gordon Joyce / Shelly J Krebs /
Abstract: Monoclonal antibodies to SARS-CoV-2 can offer prophylactic and therapeutic protection against severe disease, with particular utility for immunosuppressed and vulnerable populations. With the ...Monoclonal antibodies to SARS-CoV-2 can offer prophylactic and therapeutic protection against severe disease, with particular utility for immunosuppressed and vulnerable populations. With the constant emergence of new variants, understanding the neutralizing potency of monoclonal antibodies to dynamic spike protein epitopes is crucial. We show that a set of VH1-24-derived N-terminal domain (NTD)-directed antibodies, isolated from a convalescent donor early in the pandemic, displayed remarkable neutralization resilience against many Omicron SARS-CoV-2 variants, including BA.2, BA.5, and BQ.1.1. Neutralization potency to these Omicron variants is associated with slower off-rates to the spike protein. Structural characterization of the most potent NTD antibody, WRAIR-2008, revealed a conserved mode of interaction shared with other antibodies of the same multi-donor class. WRAIR-2008 protected mice from weight loss following BA.5 challenge and reduced infectious viral titers in the lungs. Our study highlights the retention of neutralization activity and protection of first-generation VH1-24-derived NTD-directed antibodies to specific Omicron variants and provides valuable insights into the shifting landscape of SARS-CoV-2 variants that are vulnerable to select monoclonal antibodies.
IMPORTANCE: As SARS-CoV-2 circulating variants evolve, it is important to understand the vulnerabilities of these viruses to neutralizing antibodies. Within this manuscript, we describe first- ...IMPORTANCE: As SARS-CoV-2 circulating variants evolve, it is important to understand the vulnerabilities of these viruses to neutralizing antibodies. Within this manuscript, we describe first-generation antibodies isolated following infection with WA-1 that retain viral neutralization to subsequent Omicron variants by targeting a site of viral vulnerability called the NTD. This work highlights the shifting landscape of SARS-CoV-2 variants and provides mechanistic insights into how antibodies from prior infections may play a role in preventing subsequent SARS-CoV-2 variant infections.
History
DepositionNov 15, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 22, 2025Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
H: WRAIR-2039 Fab heavy chain
L: WRAIR-2039 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,3017
Polymers46,5342
Non-polymers7675
Water6,810378
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4990 Å2
ΔGint-27 kcal/mol
Surface area19540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.422, 69.071, 102.475
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Antibody WRAIR-2039 Fab heavy chain


Mass: 23582.410 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody WRAIR-2039 Fab light chain


Mass: 22951.285 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-PE5 / 3,6,9,12,15,18,21,24-OCTAOXAHEXACOSAN-1-OL / 2-(2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHANOL / POLYETHYLENE GLYCOL PEG400


Mass: 398.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H38O9 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 378 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 2.41 Å3/Da / Density % sol: 49 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.12 M alcohol mixture (1,6-Hexanediol; 1-Butanol; 1,2-Propanediol; 2-Propanol; 1,4-Butanediol; 1,3-Propanediol), 0.1 M buffer system 1 (imidazole and MES monohydrate, pH 6.5), 30% ...Details: 0.12 M alcohol mixture (1,6-Hexanediol; 1-Butanol; 1,2-Propanediol; 2-Propanol; 1,4-Butanediol; 1,3-Propanediol), 0.1 M buffer system 1 (imidazole and MES monohydrate, pH 6.5), 30% precipitant mix 1 (40% v/v PEG 500 MME; 20% v/v PEG 20000)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 3, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.53→102.48 Å / Num. obs: 62489 / % possible obs: 92.9 % / Redundancy: 3.4 % / Biso Wilson estimate: 20.37 Å2 / CC1/2: 0.91 / Net I/σ(I): 14.7
Reflection shellResolution: 1.53→1.56 Å / Num. unique obs: 1167 / CC1/2: 0.555

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Processing

Software
NameVersionClassification
PHENIX(1.21.1_5286: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.54→53.93 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 0.02 / Phase error: 18.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1942 3152 5.25 %
Rwork0.1571 --
obs0.159 60035 89.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.54→53.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3266 0 51 378 3695
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0213426
X-RAY DIFFRACTIONf_angle_d1.7854669
X-RAY DIFFRACTIONf_dihedral_angle_d16.6191250
X-RAY DIFFRACTIONf_chiral_restr0.099533
X-RAY DIFFRACTIONf_plane_restr0.015593
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.54-1.570.3206700.24441392X-RAY DIFFRACTION51
1.57-1.590.2686930.2221811X-RAY DIFFRACTION68
1.59-1.620.23431160.20012171X-RAY DIFFRACTION80
1.62-1.650.21031250.20282361X-RAY DIFFRACTION86
1.65-1.670.28441380.21412459X-RAY DIFFRACTION90
1.68-1.710.2421540.20052456X-RAY DIFFRACTION92
1.71-1.740.1941130.1882482X-RAY DIFFRACTION90
1.74-1.780.23631330.17932481X-RAY DIFFRACTION91
1.78-1.820.20561440.16232573X-RAY DIFFRACTION94
1.82-1.870.19681460.15322574X-RAY DIFFRACTION95
1.87-1.920.17671650.15132576X-RAY DIFFRACTION95
1.92-1.970.19621530.1582574X-RAY DIFFRACTION94
1.97-2.040.21131440.15862456X-RAY DIFFRACTION90
2.04-2.110.2061530.15862630X-RAY DIFFRACTION96
2.11-2.190.21511580.15012605X-RAY DIFFRACTION96
2.19-2.290.21151310.14552645X-RAY DIFFRACTION95
2.29-2.420.20221520.15042614X-RAY DIFFRACTION95
2.42-2.570.19241550.152615X-RAY DIFFRACTION95
2.57-2.770.17371740.1492621X-RAY DIFFRACTION95
2.77-3.040.17611430.14452543X-RAY DIFFRACTION92
3.04-3.480.18951080.14772717X-RAY DIFFRACTION95
3.48-4.390.17921460.13472687X-RAY DIFFRACTION95
4.39-53.930.1821380.17932840X-RAY DIFFRACTION95
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)
11.91950.57180.26340.24010.38451.3728-0.01690.0650.07340.0295-0.02920.13770.1166-0.20920.00410.2208-0.00330.0110.22130.02440.211332.165339.97782.9409
20.8567-0.34310.24130.992-0.27611.0478-0.05480.1291-0.1249-0.08990.05720.1857-0.0322-0.1942-0.00090.1866-0.0027-0.00630.23170.00830.219330.623143.0246-7.1302
31.78980.16840.07671.07720.08580.9842-0.21340.26620.0443-0.56870.05010.12970.2684-0.0631-0.00520.3048-0.02220.01720.2486-0.0180.27136.133437.0186-13.1665
40.5867-0.45920.6931.1119-0.06031.45530.02020.0767-0.0793-0.11210.01110.17740.1285-0.1270.00030.1752-0.00750.00770.21750.01590.200231.547442.5154-5.616
51.0691-0.07680.00980.68470.13780.7499-0.0036-0.13270.19750.06220.0114-0.0772-0.07120.0083-0.02850.1442-0.00810.00080.1208-0.00220.144231.752151.691721.4273
61.2530.5025-0.10671.60660.20630.6631-0.057-0.15890.26090.00950.0632-0.0174-0.0675-0.0091-0.00510.1740.00540.00450.1820.00290.172929.713957.21421.3196
72.4717-1.1722-1.0682.30581.04771.806-0.0486-0.13290.10880.2822-0.01970.08520.134-0.1320.03190.187-0.0150.00860.1528-0.01350.149324.01949.067225.1992
81.27760.2119-0.64132.27552.09473.04180.0344-0.12230.1177-0.11420.2077-0.1626-0.1570.3885-0.06220.1744-0.0230.02850.18630.00430.186439.404567.2847-9.3686
91.81080.0274-0.36211.57870.26790.8870.0740.10990.0741-0.0184-0.045-0.0261-0.0189-0.07970.00210.15830.0075-0.00080.18060.01390.143132.90960.7051-12.708
100.88640.396-0.35631.55130.55662.07060.07640.0452-0.0971-0.02340.0536-0.1897-0.0399-0.00960.02360.17620.0018-0.0150.1564-0.00840.185939.349262.994324.8459
110.8023-0.37240.58512.7084-1.53944.00440.0528-0.10560.00420.10930.1398-0.0217-0.1385-0.13150.00080.1666-0.0021-0.00930.1522-0.01120.179239.450269.224431.7258
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'H' and (resid 1 through 17 )
2X-RAY DIFFRACTION2chain 'H' and (resid 18 through 52 )
3X-RAY DIFFRACTION3chain 'H' and (resid 52A through 72 )
4X-RAY DIFFRACTION4chain 'H' and (resid 73 through 106 )
5X-RAY DIFFRACTION5chain 'H' and (resid 107 through 157 )
6X-RAY DIFFRACTION6chain 'H' and (resid 158 through 190 )
7X-RAY DIFFRACTION7chain 'H' and (resid 191 through 215 )
8X-RAY DIFFRACTION8chain 'L' and (resid 1 through 18 )
9X-RAY DIFFRACTION9chain 'L' and (resid 19 through 106A)
10X-RAY DIFFRACTION10chain 'L' and (resid 107 through 187 )
11X-RAY DIFFRACTION11chain 'L' and (resid 188 through 212 )

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