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- PDB-7n3i: Crystal structure of the SARS-CoV-2 receptor binding domain in co... -

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Basic information

Entry
Database: PDB / ID: 7n3i
TitleCrystal structure of the SARS-CoV-2 receptor binding domain in complex with the human neutralizing antibody Fab fragment C098
Components
  • C098 Fab heavy chain
  • C098 Fab light chain
  • Spike protein S1
KeywordsIMMUNE SYSTEM/VIRAL PROTEIN / severe acute respiratory syndrome coronavirus-2 / spike protein / neutralizing antibodies / IMMUNE SYSTEM / IMMUNE SYSTEM-VIRAL PROTEIN 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / 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: 2.03 Å
AuthorsFlyak, A.I. / Bjorkman, P.J. / Barnes, C.O.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)K99AI153465 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01-AI138938-S1 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 1, 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: _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
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
C: Spike protein S1
H: C098 Fab heavy chain
L: C098 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,9964
Polymers71,7753
Non-polymers2211
Water8,647480
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)191.332, 87.842, 56.810
Angle α, β, γ (deg.)90.000, 99.790, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Spike protein S1


Mass: 24004.926 Da / Num. of mol.: 1 / Fragment: Receptor Binding Domain
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) / Strain (production host): Expi293F / References: UniProt: P0DTC2
#2: Antibody C098 Fab heavy chain


Mass: 24452.252 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / Strain (production host): Expi293F
#3: Antibody C098 Fab light chain


Mass: 23317.795 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / Strain (production host): Expi293F
#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.: 1
Source method: isolated from a genetically manipulated source
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.: 480 / 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: 3.28 Å3/Da / Density % sol: 62.47 % / Mosaicity: 0.44 °
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 0.05 M citric acid, 0.05M BIS-TRIS propane pH 5.0, 14% 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: 0.98 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: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.03→94.27 Å / Num. obs: 57277 / % possible obs: 96 % / Redundancy: 3 % / CC1/2: 0.994 / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.065 / Rrim(I) all: 0.117 / Net I/σ(I): 6.8 / Num. measured all: 173101 / Scaling rejects: 50
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
2.03-2.0830.8661283142330.5690.5831.0491.397.3
9.08-94.273.10.03920986700.9910.0270.04817.395

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7BZ5

7bz5


Resolution: 2.03→44.32 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 22.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2082 2870 5.01 %
Rwork0.179 54376 -
obs0.1805 57246 95.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 108.18 Å2 / Biso mean: 40.5783 Å2 / Biso min: 20.67 Å2
Refinement stepCycle: final / Resolution: 2.03→44.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4750 0 14 480 5244
Biso mean--64.79 44.11 -
Num. residues----622
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094876
X-RAY DIFFRACTIONf_angle_d1.096630
X-RAY DIFFRACTIONf_dihedral_angle_d18.943686
X-RAY DIFFRACTIONf_chiral_restr0.06735
X-RAY DIFFRACTIONf_plane_restr0.008856
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 21

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.03-2.060.28921370.27322581271897
2.06-2.10.34911390.26842599273897
2.1-2.140.29471360.25432596273296
2.14-2.180.30411400.24292603274396
2.18-2.220.24131220.23662590271296
2.22-2.270.28771460.22722545269194
2.27-2.320.26431200.22932398251890
2.32-2.380.23841470.21322605275297
2.38-2.450.24161460.20872620276698
2.45-2.520.23821370.20762616275398
2.52-2.60.27951240.20022637276196
2.6-2.690.23241280.19012612274096
2.69-2.80.22861390.18752453259292
2.8-2.930.22671290.18182620274996
2.93-3.080.20091480.18712612276097
3.08-3.280.22791260.17682643276997
3.28-3.530.20211330.14922599273296
3.53-3.880.17141490.1572521267093
3.88-4.450.14941230.13712689281298
4.45-5.60.14941500.13982540269093
5.6-44.320.19021510.17612697284897
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.9085-0.3141-0.1432.9142-0.24832.0018-0.01990.09480.17780.0669-0.0744-0.5784-0.2440.33110.020.2372-0.0124-0.01970.24590.02180.339177.2039.011-40.501
22.2063-1.0763-0.50961.33671.02462.2623-0.1034-0.0926-0.09380.11850.0010.07880.0036-0.11050.07240.29420.05710.01090.19070.03160.198151.2055.646-20.927
33.33780.33920.4871.52490.20192.5644-0.1054-0.34150.01170.20650.12330.33370.1615-0.1540.01780.28850.05790.0490.29530.0530.281117.62715.105-12.042
42.9294-0.8453-0.09561.90780.04042.09040.12940.4633-0.1148-0.1186-0.09390.0884-0.0743-0.3184-0.02440.2860.086-0.00970.3703-0.01210.187941.48310.435-40.752
51.9926-0.38950.11392.63390.53751.8445-0.0933-0.08470.23530.05850.06260.1184-0.10970.03540.00160.1490.023-0.00010.25430.02370.247718.40528.709-20.79
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN C AND RESID 334:527 )C334 - 527
2X-RAY DIFFRACTION2( CHAIN H AND RESID 1:118 )H1 - 118
3X-RAY DIFFRACTION3( CHAIN H AND RESID 119:214 )H119 - 214
4X-RAY DIFFRACTION4( CHAIN L AND RESID 2:108 )L2 - 108
5X-RAY DIFFRACTION5( CHAIN L AND RESID 109:214 )L109 - 214

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