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- PDB-9ii9: Crystal structure of SARS-CoV-2 neutralizing antibody K4-66 -

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Basic information

Entry
Database: PDB / ID: 9ii9
TitleCrystal structure of SARS-CoV-2 neutralizing antibody K4-66
Components(antigen-binding fragments (Fabs)) x 2
KeywordsIMMUNE SYSTEM / antigen-binding fragments (Fabs)
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsKimura, T.K. / Hashiguchi, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: EBioMedicine / Year: 2024
Title: Induction of IGHV3-53 public antibodies with broadly neutralising activity against SARS-CoV-2 including Omicron subvariants in a Delta breakthrough infection case.
Authors: Takeo Kuwata / Yu Kaku / Shashwata Biswas / Kaho Matsumoto / Mikiko Shimizu / Yoko Kawanami / Ryuta Uraki / Kyo Okazaki / Rumi Minami / Yoji Nagasaki / Mami Nagashima / Isao Yoshida / Kenji ...Authors: Takeo Kuwata / Yu Kaku / Shashwata Biswas / Kaho Matsumoto / Mikiko Shimizu / Yoko Kawanami / Ryuta Uraki / Kyo Okazaki / Rumi Minami / Yoji Nagasaki / Mami Nagashima / Isao Yoshida / Kenji Sadamasu / Kazuhisa Yoshimura / Mutsumi Ito / Maki Kiso / Seiya Yamayoshi / Masaki Imai / Terumasa Ikeda / Kei Sato / Mako Toyoda / Takamasa Ueno / Takako Inoue / Yasuhito Tanaka / Kanako Tarakado Kimura / Takao Hashiguchi / Yukihiko Sugita / Takeshi Noda / Hiroshi Morioka / Yoshihiro Kawaoka / Shuzo Matsushita / /
Abstract: BACKGROUND: Emergence of SARS-CoV-2 variants that escape neutralising antibodies hampers the development of vaccines and therapeutic antibodies against SARS-CoV-2. IGHV3-53/3-66-derived public ...BACKGROUND: Emergence of SARS-CoV-2 variants that escape neutralising antibodies hampers the development of vaccines and therapeutic antibodies against SARS-CoV-2. IGHV3-53/3-66-derived public antibodies, which are generally specific to the prototype virus and are frequently induced in infected or vaccinated individuals, show minimal affinity maturation and high potency against prototype SARS-CoV-2.
METHODS: Monoclonal antibodies isolated from a Delta breakthrough infection case were analysed for cross-neutralising activities against SARS-CoV-2 variants. The broadly neutralising antibody K4-66 ...METHODS: Monoclonal antibodies isolated from a Delta breakthrough infection case were analysed for cross-neutralising activities against SARS-CoV-2 variants. The broadly neutralising antibody K4-66 was further analysed in a hamster model, and the effect of somatic hypermutations was assessed using the inferred germline precursor.
FINDINGS: Antibodies derived from IGHV3-53/3-66 showed broader neutralising activity than antibodies derived from IGHV1-69 and other IGHV genes. IGHV3-53/3-66 antibodies neutralised the Delta variant ...FINDINGS: Antibodies derived from IGHV3-53/3-66 showed broader neutralising activity than antibodies derived from IGHV1-69 and other IGHV genes. IGHV3-53/3-66 antibodies neutralised the Delta variant better than the IGHV1-69 antibodies, suggesting that the IGHV3-53/3-66 antibodies were further maturated by Delta breakthrough infection. One IGHV3-53/3-66 antibody, K4-66, neutralised all Omicron subvariants tested, including EG.5.1, BA.2.86, and JN.1, and decreased the viral load in the lungs of hamsters infected with Omicron subvariant XBB.1.5. The importance of somatic hypermutations was demonstrated by the loss of neutralising activity of the inferred germline precursor of K4-66 against Beta and Omicron variants.
INTERPRETATION: Broadly neutralising IGHV3-53/3-66 antibodies have potential as a target for the development of effective vaccines and therapeutic antibodies against newly emerging SARS-CoV-2 variants.
FUNDING: This work was supported by grants from AMED (JP23ym0126048, JP22ym0126048, JP21ym0126048, JP23wm0125002, JP233fa627001, JP223fa627009, JP24jf0126002, and JP22fk0108572), and the JSPS ...FUNDING: This work was supported by grants from AMED (JP23ym0126048, JP22ym0126048, JP21ym0126048, JP23wm0125002, JP233fa627001, JP223fa627009, JP24jf0126002, and JP22fk0108572), and the JSPS (JP21H02970, JK23K20041, and JPJSCCA20240006).
History
DepositionJun 19, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: 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.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

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Assembly

Deposited unit
A: antigen-binding fragments (Fabs)
B: antigen-binding fragments (Fabs)
C: antigen-binding fragments (Fabs)
D: antigen-binding fragments (Fabs)


Theoretical massNumber of molelcules
Total (without water)93,0444
Polymers93,0444
Non-polymers00
Water00
1
A: antigen-binding fragments (Fabs)
B: antigen-binding fragments (Fabs)


Theoretical massNumber of molelcules
Total (without water)46,5222
Polymers46,5222
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3200 Å2
ΔGint-24 kcal/mol
Surface area19100 Å2
MethodPISA
2
C: antigen-binding fragments (Fabs)
D: antigen-binding fragments (Fabs)


Theoretical massNumber of molelcules
Total (without water)46,5222
Polymers46,5222
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2570 Å2
ΔGint-22 kcal/mol
Surface area20500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)147.450, 147.450, 154.930
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

#1: Antibody antigen-binding fragments (Fabs)


Mass: 23124.910 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Missing residues of chain C were not modeled due to weak electron density.
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody antigen-binding fragments (Fabs)


Mass: 23396.857 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: C-terminal region of chain B were not modeled due to weak electron density. Missing residues of chain D were not modeled due to weak electron density.
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: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 4.61 Å3/Da / Density % sol: 73.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1M HEPES pH 7.0-7.5, 16.5-19.0% polyethylene glycol 20000
PH range: 7.0-7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 29, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.83→49.41 Å / Num. obs: 41387 / % possible obs: 100 % / Redundancy: 81.5 % / Biso Wilson estimate: 80.55 Å2 / CC1/2: 0.998 / Net I/σ(I): 13.58
Reflection shellResolution: 2.83→2.9 Å / Num. unique obs: 6519 / CC1/2: 0.564

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Processing

Software
NameVersionClassification
REFMAC1.20.1_4487refinement
PHENIX1.20.1_4487refinement
ADDREFdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→49.41 Å / SU ML: 0.5328 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.6241
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2885 1992 5.18 %
Rwork0.2623 36461 -
obs0.2637 38453 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 88.98 Å2
Refinement stepCycle: LAST / Resolution: 2.9→49.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5784 0 0 0 5784
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00325900
X-RAY DIFFRACTIONf_angle_d0.60568091
X-RAY DIFFRACTIONf_chiral_restr0.0442953
X-RAY DIFFRACTIONf_plane_restr0.0051070
X-RAY DIFFRACTIONf_dihedral_angle_d4.9417887
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.970.46171540.4192553X-RAY DIFFRACTION100
2.97-3.050.42181560.37412535X-RAY DIFFRACTION100
3.05-3.140.36321430.33112575X-RAY DIFFRACTION100
3.14-3.240.34721380.27852538X-RAY DIFFRACTION99.96
3.24-3.360.35251350.29482591X-RAY DIFFRACTION100
3.36-3.490.31121480.29452543X-RAY DIFFRACTION100
3.49-3.650.34871450.30642576X-RAY DIFFRACTION100
3.65-3.850.29711390.24852587X-RAY DIFFRACTION100
3.85-4.090.29181230.24932624X-RAY DIFFRACTION100
4.09-4.40.25571480.22222588X-RAY DIFFRACTION100
4.4-4.840.25121450.21732618X-RAY DIFFRACTION100
4.85-5.550.28061410.23252636X-RAY DIFFRACTION100
5.55-6.980.30051340.28492684X-RAY DIFFRACTION100
6.98-49.410.21541430.25162813X-RAY DIFFRACTION99.73

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