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- PDB-7s0b: Structure of the SARS-CoV-2 RBD in complex with neutralizing anti... -

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Basic information

Entry
Database: PDB / ID: 7s0b
TitleStructure of the SARS-CoV-2 RBD in complex with neutralizing antibody N-612-056
Components
  • N-612-056 Fab Heavy Chain
  • N-612-056 Light Chain
  • Spike protein S1
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Antibody / SARS-CoV-2 / COVID-19 / mRNA Display / ANTIVIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM 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 / viral translation / host extracellular space / 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 / viral translation / host extracellular space / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell / membrane fusion / 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, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / 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 S1 subunit, receptor binding domain superfamily, 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, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / 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 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 1 (HR1) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Severe acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsTanaka, S. / Barnes, C.O. / Bjorkman, P.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01-AI138938-S1 United States
Citation
Journal: Cell Rep / Year: 2022
Title: Rapid identification of neutralizing antibodies against SARS-CoV-2 variants by mRNA display.
Authors: Shiho Tanaka / C Anders Olson / Christopher O Barnes / Wendy Higashide / Marcos Gonzalez / Justin Taft / Ashley Richardson / Marta Martin-Fernandez / Dusan Bogunovic / Priyanthi N P ...Authors: Shiho Tanaka / C Anders Olson / Christopher O Barnes / Wendy Higashide / Marcos Gonzalez / Justin Taft / Ashley Richardson / Marta Martin-Fernandez / Dusan Bogunovic / Priyanthi N P Gnanapragasam / Pamela J Bjorkman / Patricia Spilman / Kayvan Niazi / Shahrooz Rabizadeh / Patrick Soon-Shiong /
Abstract: The increasing prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with the ability to escape existing humoral protection conferred by previous infection and/or ...The increasing prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with the ability to escape existing humoral protection conferred by previous infection and/or immunization necessitates the discovery of broadly reactive neutralizing antibodies (nAbs). Utilizing mRNA display, we identify a set of antibodies against SARS-CoV-2 spike (S) proteins and characterize the structures of nAbs that recognize epitopes in the S1 subunit of the S glycoprotein. These structural studies reveal distinct binding modes for several antibodies, including the targeting of rare cryptic epitopes in the receptor-binding domain (RBD) of S that interact with angiotensin-converting enzyme 2 (ACE2) to initiate infection, as well as the S1 subdomain 1. Further, we engineer a potent ACE2-blocking nAb to sustain binding to S RBD with the E484K and L452R substitutions found in multiple SARS-CoV-2 variants. We demonstrate that mRNA display is an approach for the rapid identification of nAbs that can be used in combination to combat emerging SARS-CoV-2 variants.
#1: Journal: bioRxiv / Year: 2021
Title: Rapid Identification of Neutralizing Antibodies against SARS-CoV-2 Variants by mRNA Display.
Authors: Shiho Tanaka / C Anders Olson / Christopher O Barnes / Wendy Higashide / Marcos Gonzalez / Justin Taft / Ashley Richardson / Marta Martin-Fernandez / Dusan Bogunovic / Priyanthi N P ...Authors: Shiho Tanaka / C Anders Olson / Christopher O Barnes / Wendy Higashide / Marcos Gonzalez / Justin Taft / Ashley Richardson / Marta Martin-Fernandez / Dusan Bogunovic / Priyanthi N P Gnanapragasam / Pamela J Bjorkman / Patricia Spilman / Kayvan Niazi / Shahrooz Rabizadeh / Patrick Soon-Shiong
Abstract: The increasing prevalence of SARS-CoV-2 variants with the ability to escape existing humoral protection conferred by previous infection and/or immunization necessitates the discovery of broadly- ...The increasing prevalence of SARS-CoV-2 variants with the ability to escape existing humoral protection conferred by previous infection and/or immunization necessitates the discovery of broadly-reactive neutralizing antibodies (nAbs). Utilizing mRNA display, we identified a set of antibodies against SARS-CoV-2 spike (S) proteins and characterized the structures of nAbs that recognized epitopes in the S1 subunit of the S glycoprotein. These structural studies revealed distinct binding modes for several antibodies, including targeting of rare cryptic epitopes in the receptor-binding domain (RBD) of S that interacts with angiotensin- converting enzyme 2 (ACE2) to initiate infection, as well as the S1 subdomain 1. A potent ACE2-blocking nAb was further engineered to sustain binding to S RBD with the E484K and L452R substitutions found in multiple SARS-CoV-2 variants. We demonstrate that mRNA display is a promising approach for the rapid identification of nAbs that can be used in combination to combat emerging SARS-CoV-2 variants.
History
DepositionAug 30, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2022Group: Database references / Category: citation / citation_author
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / pdbx_initial_refinement_model
Item: _citation.journal_id_ISSN
Revision 1.3Nov 6, 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

Downloads & links

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Assembly

Deposited unit
A: N-612-056 Fab Heavy Chain
B: N-612-056 Light Chain
C: N-612-056 Fab Heavy Chain
D: N-612-056 Light Chain
E: Spike protein S1
F: Spike protein S1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)145,1808
Polymers144,7376
Non-polymers4422
Water2,252125
1
A: N-612-056 Fab Heavy Chain
B: N-612-056 Light Chain
F: Spike protein S1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,5904
Polymers72,3693
Non-polymers2211
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: N-612-056 Fab Heavy Chain
D: N-612-056 Light Chain
E: Spike protein S1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,5904
Polymers72,3693
Non-polymers2211
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)102.297, 153.656, 96.590
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 1 through 108 or resid 110 through 222))
d_2ens_1(chain "C" and (resid 1 through 108 or resid 110 through 222))
d_1ens_2(chain "B" and (resid 1 through 23 or resid 25...
d_2ens_2(chain "D" and (resid 1 through 23 or resid 25...
d_1ens_3(chain "E" and (resid 332 through 458 or resid 460 through 601))
d_2ens_3(chain "F" and (resid 332 through 458 or resid 460 through 601))

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLUPHEA1 - 108
d_12ens_1VALLYSA110 - 218
d_21ens_1GLUPHEC1 - 108
d_22ens_1VALLYSC110 - 218
d_11ens_2ASPCYSB1 - 23
d_12ens_2ALAGLUB25 - 123
d_13ens_2LEUALAB125 - 193
d_14ens_2GLUGLUB195 - 213
d_21ens_2ASPCYSD1 - 23
d_22ens_2ALAGLUD25 - 123
d_23ens_2LEUALAD125 - 193
d_24ens_2GLUGLUD195 - 213
d_11ens_3ILELYSE3 - 129
d_12ens_3ASNLYSE131 - 199
d_13ens_3NAGNAGF
d_21ens_3ILELYSG2 - 128
d_22ens_3ASNLYSG130 - 198
d_23ens_3NAGNAGH

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.999984124259, -0.00488214526635, 0.00281351864182), (0.00488096920951, -0.999987997805, -0.000424717066655), (0.00281555840383, -0.000410977626096, 0.999995951856)-51.1545491266, -0.0480947618268, 6.80409813503
2given(-0.999987843365, -0.00482987736185, -0.000992676220644), (0.00482696217705, -0.999984091556, 0.0029184023085), (-0.00100675595395, 0.00291357521998, 0.99999524875)-51.2371404927, 0.0189770226555, 6.85709151423
3given(-0.999999809217, 0.000264945788968, -0.000558005934839), (-0.000263980083773, -0.999998468707, -0.00172999925025), (-0.000558463436385, -0.00172985161774, 0.999998347865)-51.1412181759, -0.0546673693508, -6.80721630987

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Components

#1: Antibody N-612-056 Fab Heavy Chain


Mass: 24034.869 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody N-612-056 Light Chain


Mass: 23317.715 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Protein Spike protein S1


Mass: 25016.074 Da / Num. of mol.: 2
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
#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


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


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.62 Å3/Da / Density % sol: 53.1 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Lithium citrate tribasic tetrahydrate and 20% w/v polyethylene glycol 3,350

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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: Feb 10, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.9→38.96 Å / Num. obs: 34420 / % possible obs: 99.8 % / Redundancy: 6.6 % / Biso Wilson estimate: 61 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.187 / Rpim(I) all: 0.083 / Net I/σ(I): 6.4
Reflection shellResolution: 2.9→3.04 Å / Rmerge(I) obs: 1.33 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 4471 / CC1/2: 0.728 / Rpim(I) all: 0.828 / % possible all: 99.1

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7K8M

7k8m


Resolution: 2.9→38.41 Å / SU ML: 0.3773 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 32.6987
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2597 1740 5.08 %
Rwork0.2146 32483 -
obs0.217 34223 99.36 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 73.35 Å2
Refinement stepCycle: LAST / Resolution: 2.9→38.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9640 0 28 125 9793
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00459943
X-RAY DIFFRACTIONf_angle_d0.905213535
X-RAY DIFFRACTIONf_chiral_restr0.06091501
X-RAY DIFFRACTIONf_plane_restr0.00981751
X-RAY DIFFRACTIONf_dihedral_angle_d6.7391384
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AX-RAY DIFFRACTIONTorsion NCS0.651555464481
ens_2d_2BX-RAY DIFFRACTIONTorsion NCS0.786208862783
ens_3d_2EX-RAY DIFFRACTIONTorsion NCS0.774405299421
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.990.41541530.33382559X-RAY DIFFRACTION96.1
2.99-3.080.30271400.29422682X-RAY DIFFRACTION99.86
3.08-3.190.33211280.27842704X-RAY DIFFRACTION99.75
3.19-3.320.35011520.26182663X-RAY DIFFRACTION99.75
3.32-3.470.31691490.23672692X-RAY DIFFRACTION99.75
3.47-3.650.26051370.2252704X-RAY DIFFRACTION99.86
3.65-3.880.31581210.21512712X-RAY DIFFRACTION99.93
3.88-4.180.22751370.19872705X-RAY DIFFRACTION99.51
4.18-4.60.22761700.16962691X-RAY DIFFRACTION99.41
4.6-5.270.1851370.16482738X-RAY DIFFRACTION99.83
5.27-6.630.22261740.20252747X-RAY DIFFRACTION99.76
6.63-38.410.24791420.21052886X-RAY DIFFRACTION98.76
Refinement TLS params.Method: refined / Origin x: -25.5065727046 Å / Origin y: -0.028411987061 Å / Origin z: -23.8630681879 Å
111213212223313233
T0.368031229769 Å2-0.0703819870767 Å2-0.00289324495862 Å2-0.386445025238 Å20.003124082066 Å2--0.383969106119 Å2
L0.823468046464 °2-0.183623834622 °2-0.140465081858 °2-0.718717291773 °20.205314643839 °2--0.359597082639 °2
S0.000263655830351 Å °-0.225143211784 Å °0.0132150184787 Å °0.176355154528 Å °0.0223770012159 Å °-0.0596634279201 Å °0.0375119532895 Å °0.0523281247263 Å °-0.0245811660814 Å °
Refinement TLS groupSelection details: all

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