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- PDB-7wpv: Fab14 - a SARS-CoV2 RBD neutralising antibody -

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Basic information

Entry
Database: PDB / ID: 7wpv
TitleFab14 - a SARS-CoV2 RBD neutralising antibody
Components
  • Fab14 heavy chain
  • Fab14 light chain
KeywordsIMMUNE SYSTEM / SARS-Cov2 RBD neutralising antibody / PROTEIN BINDING
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.46 Å
AuthorsLin, J.Q. / El Sahili, A. / Lescar, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: Nat Commun / Year: 2022
Title: Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth.
Authors: Zhiqiang Ku / Xuping Xie / Jianqing Lin / Peng Gao / Bin Wu / Abbas El Sahili / Hang Su / Yang Liu / Xiaohua Ye / Eddie Yongjun Tan / Xin Li / Xuejun Fan / Boon Chong Goh / Wei Xiong / ...Authors: Zhiqiang Ku / Xuping Xie / Jianqing Lin / Peng Gao / Bin Wu / Abbas El Sahili / Hang Su / Yang Liu / Xiaohua Ye / Eddie Yongjun Tan / Xin Li / Xuejun Fan / Boon Chong Goh / Wei Xiong / Hannah Boyd / Antonio E Muruato / Hui Deng / Hongjie Xia / Jing Zou / Birte K Kalveram / Vineet D Menachery / Ningyan Zhang / Julien Lescar / Pei-Yong Shi / Zhiqiang An /
Abstract: One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce emergence of antibody resistance. Here we engineer two bispecific antibodies ...One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce emergence of antibody resistance. Here we engineer two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv) design (14-H-06) but not the CrossMAb design (14-crs-06) shows increased antigen-binding and virus-neutralizing activities against multiple SARS-CoV-2 variants as well as increased breadth of neutralizing activity compared to the cocktail. X-ray crystallography and cryo-EM reveal distinct binding models for individual cocktail antibodies, and computational simulations suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and multiple variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.
#1: Journal: Biorxiv / Year: 2022
Title: Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth.
Authors: Ku, Z. / Xie, X. / Lin, J. / Gao, P. / El Sahili, A. / Su, H. / Liu, Y. / Ye, X. / Li, X. / Fan, X. / Goh, B.C. / Xiong, W. / Boyd, H. / Muruato, A.E. / Deng, H. / Xia, H. / Jing, Z. / ...Authors: Ku, Z. / Xie, X. / Lin, J. / Gao, P. / El Sahili, A. / Su, H. / Liu, Y. / Ye, X. / Li, X. / Fan, X. / Goh, B.C. / Xiong, W. / Boyd, H. / Muruato, A.E. / Deng, H. / Xia, H. / Jing, Z. / Kalveram, B.K. / Menachery, V.D. / Zhang, N. / Lescar, J. / Shi, P.Y. / An, Z.
History
DepositionJan 24, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / entity / struct_keywords
Item: _entity.pdbx_description / _struct_keywords.pdbx_keywords / _struct_keywords.text
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
L: Fab14 light chain
H: Fab14 heavy chain


Theoretical massNumber of molelcules
Total (without water)48,1022
Polymers48,1022
Non-polymers00
Water1,33374
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3250 Å2
ΔGint-22 kcal/mol
Surface area19780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.700, 71.220, 96.760
Angle α, β, γ (deg.)90.000, 99.070, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11H-317-

HOH

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Components

#1: Antibody Fab14 light chain


Mass: 22518.879 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)
#2: Antibody Fab14 heavy chain


Mass: 25583.445 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 74 / 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: 2.75 Å3/Da / Density % sol: 55.24 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 0.1M Lithium Chloride, 30% PEG 4000

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Data collection

DiffractionMean temperature: 80 K / Ambient temp details: liquid nitrogen stream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9464 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 23, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9464 Å / Relative weight: 1
ReflectionResolution: 2.46→55 Å / Num. obs: 18869 / % possible obs: 98.83 % / Redundancy: 6.9 % / Biso Wilson estimate: 53.73 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.1281 / Rpim(I) all: 0.05213 / Rrim(I) all: 0.1385 / Net I/σ(I): 13.6
Reflection shellResolution: 2.46→2.548 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1.076 / Num. unique obs: 1696 / CC1/2: 0.765 / CC star: 0.931 / Rpim(I) all: 0.4418 / % possible all: 89.35

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7C01

7c01


Resolution: 2.46→48.03 Å / SU ML: 0.3277 / Cross valid method: FREE R-VALUE / σ(F): 1.21 / Phase error: 30.0057
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2563 1836 5 %
Rwork0.2104 34846 -
obs0.2126 18867 98.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 57.01 Å2
Refinement stepCycle: LAST / Resolution: 2.46→48.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3310 0 0 74 3384
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00963393
X-RAY DIFFRACTIONf_angle_d1.26974633
X-RAY DIFFRACTIONf_chiral_restr0.0674523
X-RAY DIFFRACTIONf_plane_restr0.0066591
X-RAY DIFFRACTIONf_dihedral_angle_d19.62121207
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.46-2.530.38821190.35852248X-RAY DIFFRACTION81.85
2.53-2.60.36781400.31612709X-RAY DIFFRACTION99.82
2.6-2.680.33911400.29222685X-RAY DIFFRACTION99.65
2.68-2.780.32631480.28692777X-RAY DIFFRACTION99.8
2.78-2.890.27791410.26362651X-RAY DIFFRACTION99.86
2.89-3.020.32161440.24882707X-RAY DIFFRACTION99.93
3.02-3.180.28511430.25122729X-RAY DIFFRACTION99.86
3.18-3.380.27591430.21122745X-RAY DIFFRACTION99.93
3.38-3.640.22411390.19952701X-RAY DIFFRACTION100
3.64-4.010.22891430.19642727X-RAY DIFFRACTION99.86
4.01-4.590.2381440.15972721X-RAY DIFFRACTION99.86
4.59-5.780.20591480.17972727X-RAY DIFFRACTION100
5.78-48.030.2571440.20292719X-RAY DIFFRACTION99.79

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