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- PDB-7k8r: Crystal structure of an anti-SARS-CoV-2 human neutralizing antibo... -

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Basic information

Entry
Database: PDB / ID: 7k8r
TitleCrystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C135
Components
  • C135 Fab Heavy Chain
  • C135 Fab Light Chain
KeywordsIMMUNE SYSTEM / Human Neutralizing Antibody / SARS-CoV-2 / Receptor Binding Domain / COVID-19
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsJette, C.A. / Barnes, C.O. / Bjorkman, P.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01-AI138938-S1 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P50 AI150464-13 United States
CitationJournal: Nature / Year: 2020
Title: SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
Authors: Christopher O Barnes / Claudia A Jette / Morgan E Abernathy / Kim-Marie A Dam / Shannon R Esswein / Harry B Gristick / Andrey G Malyutin / Naima G Sharaf / Kathryn E Huey-Tubman / Yu E Lee / ...Authors: Christopher O Barnes / Claudia A Jette / Morgan E Abernathy / Kim-Marie A Dam / Shannon R Esswein / Harry B Gristick / Andrey G Malyutin / Naima G Sharaf / Kathryn E Huey-Tubman / Yu E Lee / Davide F Robbiani / Michel C Nussenzweig / Anthony P West / Pamela J Bjorkman /
Abstract: The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute ...The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein show promise therapeutically and are being evaluated clinically. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.
History
DepositionSep 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 23, 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
H: C135 Fab Heavy Chain
L: C135 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,4895
Polymers47,2132
Non-polymers2763
Water54030
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4360 Å2
ΔGint-31 kcal/mol
Surface area19670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.258, 102.258, 53.325
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number76
Space group name H-MP41
Space group name HallP4w
Symmetry operation#1: x,y,z
#2: -y,x,z+1/4
#3: y,-x,z+3/4
#4: -x,-y,z+1/2

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Components

#1: Antibody C135 Fab Heavy Chain


Mass: 23686.502 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#2: Antibody C135 Fab Light Chain


Mass: 23526.041 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 30 / 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: 2.88 Å3/Da / Density % sol: 57.31 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 0.04 M potassium phosphate, 16% w/v PEG8000, 20% v/v glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 19, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→47.28 Å / Num. obs: 72349 / % possible obs: 99.4 % / Redundancy: 6.8 % / Biso Wilson estimate: 52.56 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.035 / Net I/σ(I): 6.8
Reflection shellResolution: 2→2.07 Å / Rmerge(I) obs: 2.13 / Num. unique obs: 3071 / CC1/2: 0.305 / Rpim(I) all: 0.889

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Blu-Icedata collection
XDSdata reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 7BZ5

7bz5


Resolution: 2→47.28 Å / SU ML: 0.3267 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.6491
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2367 3860 5.34 %
Rwork0.195 68489 -
obs0.1972 72349 99.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 59.85 Å2
Refinement stepCycle: LAST / Resolution: 2→47.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3322 0 0 30 3352
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01283411
X-RAY DIFFRACTIONf_angle_d1.17364638
X-RAY DIFFRACTIONf_chiral_restr0.0616518
X-RAY DIFFRACTIONf_plane_restr0.0073592
X-RAY DIFFRACTIONf_dihedral_angle_d19.97031216
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.020.36241230.38112260X-RAY DIFFRACTION90.95
2.02-2.050.33871420.35952450X-RAY DIFFRACTION98.74
2.05-2.080.33681340.3472391X-RAY DIFFRACTION99.14
2.08-2.110.34431350.33132461X-RAY DIFFRACTION99.5
2.11-2.140.32991400.32112466X-RAY DIFFRACTION97.02
2.14-2.170.33751360.3132388X-RAY DIFFRACTION99.53
2.17-2.20.34441420.31762458X-RAY DIFFRACTION100
2.2-2.240.36161420.31162450X-RAY DIFFRACTION99.42
2.24-2.280.32591360.30312474X-RAY DIFFRACTION99.92
2.28-2.320.31011440.27392465X-RAY DIFFRACTION99.81
2.32-2.360.30511340.26892443X-RAY DIFFRACTION99.65
2.36-2.410.30961460.26172502X-RAY DIFFRACTION100
2.41-2.460.24761380.24782440X-RAY DIFFRACTION99.81
2.46-2.520.32121360.24522462X-RAY DIFFRACTION100
2.52-2.580.27441390.23632472X-RAY DIFFRACTION99.89
2.58-2.650.271380.23892449X-RAY DIFFRACTION99.92
2.65-2.730.33941400.23982484X-RAY DIFFRACTION99.92
2.73-2.820.27271420.23432472X-RAY DIFFRACTION100
2.82-2.920.24531420.22162438X-RAY DIFFRACTION100
2.92-3.040.27311390.23082447X-RAY DIFFRACTION99.19
3.04-3.170.33461420.24152399X-RAY DIFFRACTION97.51
3.18-3.340.26111480.21882458X-RAY DIFFRACTION99.89
3.34-3.550.31861270.20382486X-RAY DIFFRACTION100
3.55-3.830.23161300.19092473X-RAY DIFFRACTION99.96
3.83-4.210.17051370.15822462X-RAY DIFFRACTION100
4.21-4.820.16651500.12622461X-RAY DIFFRACTION99.92
4.82-6.070.16141290.13442416X-RAY DIFFRACTION97.7
6.07-47.280.20061290.15432462X-RAY DIFFRACTION99.65

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