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- PDB-7r8l: Structure of the SARS-CoV-2 RBD in complex with neutralizing anti... -

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Basic information

Entry
Database: PDB / ID: 7r8l
TitleStructure of the SARS-CoV-2 RBD in complex with neutralizing antibody C099 and CR3022
Components
  • C099 Fab Heavy Chain
  • C099 Fab Light Chain
  • CR3022 Fab heavy chain
  • CR3022 Fab light chain
  • Spike protein S1
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / SARS-CoV-2 / receptor binding domain / RBD / neutralizing antibody / COVID-19 / spike / ANTIVIRAL PROTEIN / 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 / entry receptor-mediated virion attachment to host cell ...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 / entry receptor-mediated virion attachment to host cell / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / 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 / symbiont-mediated suppression of host innate immune response / 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 / 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 / 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 speciesHomo sapiens (human)
Severe acute respiratory syndrome coronavirus 2
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsBarnes, 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-AI138398 United States
Citation
Journal: Immunity / Year: 2021
Title: Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations.
Authors: Frauke Muecksch / Yiska Weisblum / Christopher O Barnes / Fabian Schmidt / Dennis Schaefer-Babajew / Zijun Wang / Julio C C Lorenzi / Andrew I Flyak / Andrew T DeLaitsch / Kathryn E Huey- ...Authors: Frauke Muecksch / Yiska Weisblum / Christopher O Barnes / Fabian Schmidt / Dennis Schaefer-Babajew / Zijun Wang / Julio C C Lorenzi / Andrew I Flyak / Andrew T DeLaitsch / Kathryn E Huey-Tubman / Shurong Hou / Celia A Schiffer / Christian Gaebler / Justin Da Silva / Daniel Poston / Shlomo Finkin / Alice Cho / Melissa Cipolla / Thiago Y Oliveira / Katrina G Millard / Victor Ramos / Anna Gazumyan / Magdalena Rutkowska / Marina Caskey / Michel C Nussenzweig / Pamela J Bjorkman / Theodora Hatziioannou / Paul D Bieniasz /
Abstract: Antibodies elicited by infection accumulate somatic mutations in germinal centers that can increase affinity for cognate antigens. We analyzed 6 independent groups of clonally related severe acute ...Antibodies elicited by infection accumulate somatic mutations in germinal centers that can increase affinity for cognate antigens. We analyzed 6 independent groups of clonally related severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) Spike receptor-binding domain (RBD)-specific antibodies from 5 individuals shortly after infection and later in convalescence to determine the impact of maturation over months. In addition to increased affinity and neutralization potency, antibody evolution changed the mutational pathways for the acquisition of viral resistance and restricted neutralization escape options. For some antibodies, maturation imposed a requirement for multiple substitutions to enable escape. For certain antibodies, affinity maturation enabled the neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.
#1: Journal: bioRxiv / Year: 2021
Title: Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies.
Authors: Frauke Muecksch / Yiska Weisblum / Christopher O Barnes / Fabian Schmidt / Dennis Schaefer-Babajew / Julio C C Lorenzi / Andrew I Flyak / Andrew T DeLaitsch / Kathryn E Huey-Tubman / Shurong ...Authors: Frauke Muecksch / Yiska Weisblum / Christopher O Barnes / Fabian Schmidt / Dennis Schaefer-Babajew / Julio C C Lorenzi / Andrew I Flyak / Andrew T DeLaitsch / Kathryn E Huey-Tubman / Shurong Hou / Celia A Schiffer / Christian Gaebler / Zijun Wang / Justin Da Silva / Daniel Poston / Shlomo Finkin / Alice Cho / Melissa Cipolla / Thiago Y Oliveira / Katrina G Millard / Victor Ramos / Anna Gazumyan / Magdalena Rutkowska / Marina Caskey / Michel C Nussenzweig / Pamela J Bjorkman / Theodora Hatziioannou / Paul D Bieniasz /
Abstract: Antibodies elicited in response to infection undergo somatic mutation in germinal centers that can result in higher affinity for the cognate antigen. To determine the effects of somatic mutation on ...Antibodies elicited in response to infection undergo somatic mutation in germinal centers that can result in higher affinity for the cognate antigen. To determine the effects of somatic mutation on the properties of SARS-CoV-2 spike receptor-binding domain (RBD)-specific antibodies, we analyzed six independent antibody lineages. As well as increased neutralization potency, antibody evolution changed pathways for acquisition of resistance and, in some cases, restricted the range of neutralization escape options. For some antibodies, maturation apparently imposed a requirement for multiple spike mutations to enable escape. For certain antibody lineages, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.
History
DepositionJun 26, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 4, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 11, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Aug 25, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: C099 Fab Heavy Chain
L: C099 Fab Light Chain
E: Spike protein S1
C: CR3022 Fab heavy chain
D: CR3022 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,4436
Polymers115,7105
Non-polymers7331
Water1,856103
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, monomeric disperse peak
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)109.947, 109.947, 228.554
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw

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Components

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Antibody , 4 types, 4 molecules HLCD

#1: Antibody C099 Fab Heavy Chain


Mass: 22909.693 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody C099 Fab Light Chain


Mass: 23066.643 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody CR3022 Fab heavy chain


Mass: 23455.420 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody CR3022 Fab light chain


Mass: 24376.963 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Protein / Sugars / Non-polymers , 3 types, 105 molecules E

#3: Protein Spike protein S1


Mass: 21901.570 Da / Num. of mol.: 1
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: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 732.682 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1221m-1a_1-5]/1-1-2-3/a4-b1_a6-d1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.04 Å3/Da / Density % sol: 59.54 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.1M Sodium cacodylate, 40% 2-Methyl-2,4-pentanediol (MPD), and 5% PEG8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97984 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: 0.97984 Å / Relative weight: 1
ReflectionResolution: 2.6→39.62 Å / Num. obs: 44010 / % possible obs: 100 % / Redundancy: 12.9 % / Biso Wilson estimate: 58.49 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.257 / Rpim(I) all: 0.074 / Rrim(I) all: 0.268 / Net I/σ(I): 8.9 / Num. measured all: 569763 / Scaling rejects: 351
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.6-2.712.64.1465696145360.3511.2194.3271.1100
9.73-39.6210.90.099106619740.9960.0310.10420.398.7

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
Aimless0.7.4data scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7BZ5

7bz5


Resolution: 2.6→39.62 Å / SU ML: 0.2846 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.2244
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2286 2211 5.04 %
Rwork0.1797 41653 -
obs0.1821 43864 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 59.94 Å2
Refinement stepCycle: LAST / Resolution: 2.6→39.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8099 0 49 103 8251
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00858339
X-RAY DIFFRACTIONf_angle_d1.033711338
X-RAY DIFFRACTIONf_chiral_restr0.05531273
X-RAY DIFFRACTIONf_plane_restr0.00751448
X-RAY DIFFRACTIONf_dihedral_angle_d7.03011179
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.660.36251310.29932469X-RAY DIFFRACTION97.34
2.66-2.720.28081510.26662556X-RAY DIFFRACTION100
2.72-2.790.3191430.25832553X-RAY DIFFRACTION100
2.79-2.860.2871300.24322561X-RAY DIFFRACTION100
2.86-2.950.29411300.23352582X-RAY DIFFRACTION100
2.95-3.040.25731500.22462561X-RAY DIFFRACTION100
3.04-3.150.28011400.21552572X-RAY DIFFRACTION100
3.15-3.280.311370.20332566X-RAY DIFFRACTION100
3.28-3.420.2791290.2012599X-RAY DIFFRACTION100
3.42-3.60.25661270.19132601X-RAY DIFFRACTION100
3.6-3.830.23011420.18812586X-RAY DIFFRACTION100
3.83-4.130.23041380.15962618X-RAY DIFFRACTION100
4.13-4.540.20031500.14042624X-RAY DIFFRACTION100
4.54-5.20.17961520.13632646X-RAY DIFFRACTION100
5.2-6.540.19461200.17272702X-RAY DIFFRACTION99.96
6.54-39.620.17381410.15642857X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -6.96726183771 Å / Origin y: 8.96960092739 Å / Origin z: 37.1893077731 Å
111213212223313233
T0.419369050855 Å2-0.0170225958912 Å20.0116306175346 Å2-0.434839840676 Å20.00221885390537 Å2--0.39426834601 Å2
L0.165946864148 °20.0552452096727 °20.106558384497 °2-0.145386298164 °2-0.0311171912282 °2--0.0461597311197 °2
S0.0437825487687 Å °0.00863871748011 Å °0.000810595247421 Å °-0.0256332777591 Å °0.00472546986239 Å °-0.000314386756725 Å °-0.0326540077085 Å °0.012491968147 Å °-5.35381166052E-7 Å °
Refinement TLS groupSelection details: all

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