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- PDB-7wph: SARS-CoV2 RBD bound to Fab06 -

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Basic information

Entry
Database: PDB / ID: 7wph
TitleSARS-CoV2 RBD bound to Fab06
Components
  • FAB06 light chain
  • Fab06 heavy chain
  • Spike protein S1
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / SARS-Cov2 RBD / antibody / PROTEIN BINDING / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / host cell endoplasmic reticulum-Golgi intermediate compartment membrane ...Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / entry receptor-mediated virion attachment to host cell / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / membrane fusion / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / receptor ligand activity / host cell surface receptor binding / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / membrane / identical protein binding / plasma membrane
Similarity search - Function
Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike glycoprotein, betacoronavirus / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike glycoprotein, betacoronavirus / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, 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, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2 / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.89 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 23, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Spike protein S1
B: Spike protein S1
D: FAB06 light chain
E: Fab06 heavy chain
H: Fab06 heavy chain
L: FAB06 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)155,6498
Polymers155,2076
Non-polymers4422
Water1,71195
1
A: Spike protein S1
D: FAB06 light chain
E: Fab06 heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,8254
Polymers77,6033
Non-polymers2211
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Spike protein S1
H: Fab06 heavy chain
L: FAB06 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,8254
Polymers77,6033
Non-polymers2211
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.170, 266.350, 112.610
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 333 through 527 or resid 1307))
d_2ens_1chain "B"
d_1ens_2(chain "D" and resid 2 through 212)
d_2ens_2chain "L"
d_1ens_3chain "E"
d_2ens_3(chain "H" and (resid 1 through 134 or resid 142 through 217))

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1THRPROA1 - 195
d_12ens_1NAGNAGB
d_21ens_1THRPROC1 - 195
d_22ens_1NAGNAGD
d_11ens_2ALATHRE2 - 212
d_21ens_2ALATHRH1 - 211
d_11ens_3GLNLYSF1 - 210
d_21ens_3GLNPROG1 - 134
d_22ens_3GLYLYSG138 - 213

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.645252830886, -0.746313481858, 0.163294124302), (-0.751311038629, 0.581148818102, -0.312726357145), (0.138493709129, -0.324472245372, -0.935701477243)48.2973410478, 62.1919575956, 81.1994457085
2given(-0.622582467888, -0.774717676494, 0.110469871032), (-0.765321699406, 0.573313755909, -0.292564580397), (0.163321055274, -0.266690567912, -0.949843341763)51.8335743099, 61.9025065132, 79.2356204836
3given(-0.625605537919, -0.769933844034, 0.125775938621), (-0.761803439657, 0.568160921796, -0.311205215688), (0.168146454771, -0.290508249031, -0.941982869798)51.1309172068, 63.2823632189, 79.3914980377

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Components

#1: Protein Spike protein S1


Mass: 30823.617 Da / Num. of mol.: 2 / Fragment: RBD
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: S, 2 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: P0DTC2
#2: Antibody FAB06 light chain


Mass: 22664.959 Da / Num. of mol.: 2
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: Antibody Fab06 heavy chain


Mass: 24114.854 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 95 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.42 Å3/Da / Density % sol: 49.25 % / Description: thin plate
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 0.2M magnesium formate dihydrate, 20% w/v PEG 3350

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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: Jun 30, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9464 Å / Relative weight: 1
ReflectionResolution: 2.89→55 Å / Num. obs: 34904 / % possible obs: 99.81 % / Redundancy: 10.4 % / Biso Wilson estimate: 63.21 Å2 / CC1/2: 0.994 / CC star: 0.998 / Rpim(I) all: 0.1006 / Rrim(I) all: 0.3316 / Net I/σ(I): 8.31
Reflection shellResolution: 2.89→2.993 Å / Mean I/σ(I) obs: 1.22 / Num. unique obs: 3389 / CC1/2: 0.522 / % possible all: 96.7

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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: 2.89→48.15 Å / SU ML: 0.5441 / Cross valid method: FREE R-VALUE / σ(F): 1.25 / Phase error: 31.178
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2694 3261 5 %
Rwork0.2286 61923 -
obs0.2306 34898 99.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 67.21 Å2
Refinement stepCycle: LAST / Resolution: 2.89→48.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9411 0 28 97 9536
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01179684
X-RAY DIFFRACTIONf_angle_d1.552913211
X-RAY DIFFRACTIONf_chiral_restr0.1751474
X-RAY DIFFRACTIONf_plane_restr0.00771698
X-RAY DIFFRACTIONf_dihedral_angle_d16.43563405
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2BX-RAY DIFFRACTIONTorsion NCS1.20174200543
ens_2d_2LX-RAY DIFFRACTIONTorsion NCS0.996851817106
ens_3d_2HX-RAY DIFFRACTIONTorsion NCS0.788422406041
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.89-2.930.44511250.38262353X-RAY DIFFRACTION85.92
2.93-2.970.3941420.34992706X-RAY DIFFRACTION99.96
2.97-3.020.39271430.34632687X-RAY DIFFRACTION99.86
3.02-3.080.40321410.35112732X-RAY DIFFRACTION99.97
3.08-3.130.37281410.33622744X-RAY DIFFRACTION99.97
3.13-3.190.34111440.31112661X-RAY DIFFRACTION99.89
3.19-3.260.33541380.30662688X-RAY DIFFRACTION100
3.26-3.330.36681470.27662772X-RAY DIFFRACTION99.86
3.33-3.40.36841400.26772628X-RAY DIFFRACTION99.96
3.4-3.490.27441460.24962720X-RAY DIFFRACTION99.93
3.49-3.580.28971450.24692757X-RAY DIFFRACTION99.9
3.58-3.690.25561400.24532648X-RAY DIFFRACTION99.93
3.69-3.810.2621380.22182716X-RAY DIFFRACTION100
3.81-3.940.22851420.2172719X-RAY DIFFRACTION100
3.94-4.10.23681420.2112716X-RAY DIFFRACTION100
4.1-4.290.24281390.18992725X-RAY DIFFRACTION100
4.29-4.510.25861480.1782739X-RAY DIFFRACTION100
4.51-4.80.21351370.18142663X-RAY DIFFRACTION100
4.8-5.170.25681400.19162728X-RAY DIFFRACTION100
5.17-5.690.22271470.19622695X-RAY DIFFRACTION99.89
5.69-6.510.21961480.20692720X-RAY DIFFRACTION100
6.51-8.190.19141420.20342721X-RAY DIFFRACTION100
8.19-48.150.25891460.20062685X-RAY DIFFRACTION99.61

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