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- PDB-7n3g: Crystal structure of an anti-SARS-CoV-2 human neutralizing antibo... -

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Basic information

Entry
Database: PDB / ID: 7n3g
TitleCrystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment C098
Components
  • C098 Fab Heavy Chain
  • C098 Fab Light Chain
KeywordsIMMUNE SYSTEM / severe acute respiratory syndrome coronavirus-2 / spike protein / neutralizing antibodies
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.42 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
H: C098 Fab Heavy Chain
L: C098 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)47,7702
Polymers47,7702
Non-polymers00
Water6,053336
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3340 Å2
ΔGint-23 kcal/mol
Surface area19180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.100, 88.100, 216.246
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11H-431-

HOH

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Components

#1: 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
#2: 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
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 336 / Source method: isolated from a natural source / Formula: H2O

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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: 2.54 Å3/Da / Density % sol: 51.49 % / Mosaicity: 0.37 °
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 2.0 M ammonium sulfate, citric acid pH 3.5

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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: Jan 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.42→76.3 Å / Num. obs: 93013 / % possible obs: 99.6 % / Redundancy: 16.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.079 / Rpim(I) all: 0.02 / Rrim(I) all: 0.081 / Net I/σ(I): 17.4 / Num. measured all: 1535148 / Scaling rejects: 581
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
1.42-1.45172.0797584344640.6370.5142.1431.699.2
7.79-76.317.10.037123277210.9990.0090.03851.4100

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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: 6XC4

6xc4


Resolution: 1.42→44.05 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 20.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2052 4566 4.92 %
Rwork0.1855 88320 -
obs0.1864 92886 99.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 118.5 Å2 / Biso mean: 34.3795 Å2 / Biso min: 12.3 Å2
Refinement stepCycle: final / Resolution: 1.42→44.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3243 0 0 336 3579
Biso mean---36.38 -
Num. residues----431
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013447
X-RAY DIFFRACTIONf_angle_d1.1694725
X-RAY DIFFRACTIONf_dihedral_angle_d20.2641265
X-RAY DIFFRACTIONf_chiral_restr0.09539
X-RAY DIFFRACTIONf_plane_restr0.007611
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.42-1.440.30731490.28242867301699
1.44-1.460.33651340.27982864299899
1.46-1.470.30591430.26542884302799
1.47-1.490.26811130.25622948306199
1.49-1.510.26061640.24972863302799
1.51-1.530.28611420.23762891303399
1.53-1.550.25461500.23242902305299
1.55-1.580.20541510.22222914306599
1.58-1.60.25661500.21572912306299
1.6-1.630.24861500.214728963046100
1.63-1.660.21751670.20228973064100
1.66-1.690.23481440.19528993043100
1.69-1.720.22551420.189229413083100
1.72-1.750.2251490.184429433092100
1.75-1.790.22891440.182829173061100
1.79-1.830.171670.185829253092100
1.83-1.880.21311690.17782887305699
1.88-1.930.17891370.181229593096100
1.93-1.990.1961480.172629293077100
1.99-2.050.17851460.166129673113100
2.05-2.130.18431750.163229003075100
2.13-2.210.17991710.163529603131100
2.21-2.310.211610.16929763137100
2.31-2.430.15571540.16932921307599
2.43-2.590.20461780.175729893167100
2.59-2.780.19211690.172829773146100
2.79-3.070.18831390.174330453184100
3.07-3.510.19191450.17362967311297
3.51-4.420.17891510.164231303281100
4.42-44.050.25211640.22163250341498
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)
11.94781.32240.01782.4968-0.60831.5979-0.08830.0223-0.0271-0.1340.0487-0.09690.0201-0.04120.03870.1284-0.015-0.0030.12220.00440.113436.508-48.08418.751
24.449-0.7952.41972.1719-0.9242.3845-0.204-0.8955-0.00360.58620.3625-0.121-0.2438-0.2679-0.21320.4080.1016-0.09610.4136-0.05940.322317.97-23.8857.359
33.0705-0.12051.12561.7981-0.09142.56210.02360.0361-0.13390.003-0.0779-0.063-0.04450.16670.06210.142-0.0012-0.00340.09620.02940.103425.238-58.3281.659
42.21710.45990.25922.7450.56782.45830.00210.0120.34360.13940.0399-0.3189-0.23450.2633-0.00670.19470.0332-0.05710.17450.0130.266918.17-23.498-8.666
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN H AND RESID 1:118 )H1 - 118
2X-RAY DIFFRACTION2( CHAIN H AND RESID 119:215 )H119 - 215
3X-RAY DIFFRACTION3( CHAIN L AND RESID 1:108 )L1 - 108
4X-RAY DIFFRACTION4( CHAIN L AND RESID 109:214 )L109 - 214

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