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- PDB-7uzc: Structure of the SARS-CoV-2 RBD in complex with the mouse antibod... -

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Basic information

Entry
Database: PDB / ID: 7uzc
TitleStructure of the SARS-CoV-2 RBD in complex with the mouse antibody Fab fragment, M8a-34
Components
  • M8a-34 Fab heavy chain
  • M8a-34 Fab light chain
  • Spike protein S1
KeywordsIMMUNE SYSTEM/VIRAL PROTEIN / immune system / neutralizing antibody / IMMUNE SYSTEM-VIRAL PROTEIN complex
Function / homology
Function and homology information


symbiont-mediated disruption of host tissue / Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / viral translation / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion ...symbiont-mediated disruption of host tissue / Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / viral translation / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / membrane fusion / entry receptor-mediated virion attachment to host cell / Attachment and Entry / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / receptor ligand activity / endocytosis involved in viral entry into host cell / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / symbiont entry into host cell / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / identical protein binding / membrane / 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 / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, 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 superfamily, coronavirus / Spike glycoprotein S2, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2
Mus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsFan, C. / Bjorkman, P.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)1P01AI138938-S1 United States
CitationJournal: Immunity / Year: 2022
Title: Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes.
Authors: Chengcheng Fan / Alexander A Cohen / Miso Park / Alfur Fu-Hsin Hung / Jennifer R Keeffe / Priyanthi N P Gnanapragasam / Yu E Lee / Han Gao / Leesa M Kakutani / Ziyan Wu / Harry Kleanthous / ...Authors: Chengcheng Fan / Alexander A Cohen / Miso Park / Alfur Fu-Hsin Hung / Jennifer R Keeffe / Priyanthi N P Gnanapragasam / Yu E Lee / Han Gao / Leesa M Kakutani / Ziyan Wu / Harry Kleanthous / Kathryn E Malecek / John C Williams / Pamela J Bjorkman /
Abstract: Increased immune evasion by SARS-CoV-2 variants of concern highlights the need for new therapeutic neutralizing antibodies. Immunization with nanoparticles co-displaying spike receptor-binding ...Increased immune evasion by SARS-CoV-2 variants of concern highlights the need for new therapeutic neutralizing antibodies. Immunization with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicits cross-reactive polyclonal antibodies against conserved sarbecovirus RBD epitopes. Here, we identified monoclonal antibodies (mAbs) capable of cross-reactive binding and neutralization of animal sarbecoviruses and SARS-CoV-2 variants by screening single mouse B cells secreting IgGs that bind two or more sarbecovirus RBDs. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes. Structural analyses revealed neutralization mechanisms, potentials for intra-spike trimer cross-linking by IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb-resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticle vaccination to generate and identify therapeutic pan-sarbecovirus and pan-variant mAbs.
History
DepositionMay 8, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2023Group: Derived calculations / Refinement description / Structure summary
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_oper_list / refine_ls_restr_ncs / struct_keywords / struct_ncs_dom / struct_ncs_dom_lim / struct_ncs_oper
Item: _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list ..._pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
E: M8a-34 Fab heavy chain
F: M8a-34 Fab light chain
H: M8a-34 Fab heavy chain
L: M8a-34 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,5748
Polymers150,9156
Non-polymers1,6602
Water8,773487
1
A: Spike protein S1
H: M8a-34 Fab heavy chain
L: M8a-34 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,3684
Polymers75,4573
Non-polymers9111
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Spike protein S1
E: M8a-34 Fab heavy chain
F: M8a-34 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,2064
Polymers75,4573
Non-polymers7491
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.470, 165.165, 93.715
Angle α, β, γ (deg.)90.000, 106.630, 90.000
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Antibody , 2 types, 4 molecules EHFL

#2: Antibody M8a-34 Fab heavy chain


Mass: 25507.477 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Antibody M8a-34 Fab light chain


Mass: 23955.605 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)

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Protein / Non-polymers , 2 types, 489 molecules AB

#1: Protein Spike protein S1


Mass: 25994.311 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 / Production host: Homo sapiens (human) / References: UniProt: P0DTC2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 487 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 2 types, 2 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c6-d1_d3-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#5: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE

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Details

Has ligand of interestY
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: 2.68 Å3/Da / Density % sol: 54.05 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 2% v/v tacsimate pH 4.0, 0.1 M sodium acetate trihydrate pH 4.6, 16 % PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 19, 2021
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.2→39.45 Å / Num. obs: 79165 / % possible obs: 98.6 % / Redundancy: 7 % / Biso Wilson estimate: 41.38 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.12 / Rpim(I) all: 0.048 / Rrim(I) all: 0.13 / Χ2: 0.98 / Net I/σ(I): 9.9
Reflection shellResolution: 2.2→2.24 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1.611 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 4396 / CC1/2: 0.608 / Rpim(I) all: 0.663 / Rrim(I) all: 1.746 / Χ2: 0.96 / % possible all: 96.4

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
Blu-Icedata collection
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7SC1

7sc1


Resolution: 2.2→39.23 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2433 1998 2.53 %
Rwork0.1715 77117 -
obs0.1733 79115 98.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 110.99 Å2 / Biso mean: 47.0176 Å2 / Biso min: 21.89 Å2
Refinement stepCycle: final / Resolution: 2.2→39.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9884 0 111 487 10482
Biso mean--84.95 44.27 -
Num. residues----1278
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2-2.250.32691410.2755421556297
2.25-2.310.31671380.25355389552797
2.31-2.380.32881410.23555565570699
2.38-2.460.33251470.22255525567299
2.46-2.550.2751440.20515511565599
2.55-2.650.28211400.19135505564599
2.65-2.770.24021440.18535543568799
2.77-2.920.28361430.1975425556898
2.92-3.10.29441440.20495561570599
3.1-3.340.29371440.19755543568799
3.34-3.670.29621420.185461560398
3.67-4.20.19961460.155576572299
4.21-5.30.1731440.12065526567099
5.3-39.230.18591400.14045566570698

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