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- PDB-7k8o: Crystal structure of an anti-SARS-CoV-2 human neutralizing antibo... -

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Basic information

Entry
Database: PDB / ID: 7k8o
TitleCrystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C002
Components
  • C002 Fab Heavy Chain
  • C002 Fab Light Chain
KeywordsIMMUNE SYSTEM / Human Neutralizing Antibody / SARS-CoV-2 / Receptor Binding Domain / COVID-19
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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 1.1Oct 28, 2020Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.2Jan 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 1.3Oct 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 1.4Oct 9, 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
H: C002 Fab Heavy Chain
L: C002 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,52911
Polymers48,6962
Non-polymers8339
Water1,13563
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5210 Å2
ΔGint-28 kcal/mol
Surface area20200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.271, 92.271, 130.863
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z

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Components

#1: Antibody C002 Fab Heavy Chain


Mass: 25370.459 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 C002 Fab Light Chain


Mass: 23325.807 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.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 3.3 Å3/Da / Density % sol: 62.75 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 0.2 M lithium sulfate monohydrate, 20% w/v PEG3350

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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: 1.92→34.1 Å / Num. obs: 90103 / % possible obs: 99.24 % / Redundancy: 9.9 % / Biso Wilson estimate: 48.69 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.024 / Net I/σ(I): 13
Reflection shellResolution: 1.92→1.99 Å / Rmerge(I) obs: 1.48 / Num. unique obs: 413 / CC1/2: 0.807 / Rpim(I) all: 0.334 / % possible all: 99.7

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Processing

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

7bz5


Resolution: 1.95→34.1 Å / SU ML: 0.3116 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 35.5722
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2372 3554 3.94 %
Rwork0.2036 86549 -
obs0.2049 90103 99.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 72.14 Å2
Refinement stepCycle: LAST / Resolution: 1.95→34.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3339 0 48 63 3450
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00463456
X-RAY DIFFRACTIONf_angle_d0.71254687
X-RAY DIFFRACTIONf_chiral_restr0.048527
X-RAY DIFFRACTIONf_plane_restr0.0044594
X-RAY DIFFRACTIONf_dihedral_angle_d17.67771242
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.980.63321440.53213422X-RAY DIFFRACTION99.28
1.98-20.50781470.49293476X-RAY DIFFRACTION99.1
2-2.030.41911400.43673409X-RAY DIFFRACTION99.13
2.03-2.070.39021430.41073470X-RAY DIFFRACTION99.01
2.07-2.10.38661370.37193469X-RAY DIFFRACTION98.98
2.1-2.140.43081400.35243446X-RAY DIFFRACTION98.76
2.14-2.180.34311390.32493398X-RAY DIFFRACTION98.5
2.18-2.220.29811390.2873495X-RAY DIFFRACTION98.56
2.22-2.260.32271430.2663424X-RAY DIFFRACTION98.84
2.26-2.310.30661320.26113493X-RAY DIFFRACTION99.21
2.31-2.370.28561460.25033431X-RAY DIFFRACTION98.78
2.37-2.420.37181400.24633479X-RAY DIFFRACTION99.42
2.42-2.490.27211340.23363443X-RAY DIFFRACTION98.65
2.49-2.560.2651440.23453454X-RAY DIFFRACTION98.71
2.56-2.650.28881390.24233442X-RAY DIFFRACTION98.54
2.65-2.740.29671400.25483429X-RAY DIFFRACTION99.42
2.74-2.850.3211480.25013489X-RAY DIFFRACTION99.89
2.85-2.980.28071440.23693528X-RAY DIFFRACTION99.59
2.98-3.140.26461420.243471X-RAY DIFFRACTION99.86
3.14-3.330.281420.22693485X-RAY DIFFRACTION99.86
3.33-3.590.21871330.18963449X-RAY DIFFRACTION99.72
3.59-3.950.24271500.19053494X-RAY DIFFRACTION99.92
3.95-4.520.17741460.14783500X-RAY DIFFRACTION100
4.52-5.690.17151480.14043483X-RAY DIFFRACTION99.94
5.7-34.10.18771540.1713470X-RAY DIFFRACTION99.67
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)
12.81643603306-0.8154179042042.990142086430.862693292927-0.2060008779123.595780312080.1947660538150.458013611002-0.0567920004459-0.2439949593140.0013249400563-0.0595612516210.4080986470550.6428291862820.0002079211392740.655577801922-0.05624690926480.01750493514710.743841217078-0.0411026378480.674706939789-25.932101221527.1133513356-30.3213374496
22.93161986623-0.371832011678-0.9812660473320.769498521105-0.8274277849811.57082504234-0.3642795245480.179931704437-0.625868504320.228188052099-0.122822089439-0.04606569363841.06373384818-0.2081224992730.003400536782030.988292767982-0.1444064914620.1559598002550.780999537447-0.1066760811390.863456527593-14.886594994725.8851263153.51906897757
33.01470136575-0.3301600314470.1614300935671.398595565350.6329634047683.40077449207-0.0918424457006-0.1622254050490.0853185586928-0.06655039851730.1145885932920.0598123935189-0.163857961640.02396221211010.001675363653250.491817069316-0.115064349384-0.001813544738270.566666893159-0.002303330074540.635254772881-39.203916579141.6545035157-19.6675456754
44.730498793920.160921829275-0.4377416998011.4183611175-0.01072185909242.337621417930.00805757394917-0.2826595754769.81545933714E-60.081333506705-0.112167569975-0.03950207071410.182105779429-0.1268021817950.001592665701220.602355871708-0.02211439049380.02254625512960.807157104825-0.07950833659470.64442076113-12.037122554441.09743367054.22286938117
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'H' and (resid 1 through 122 )
2X-RAY DIFFRACTION2chain 'H' and (resid 123 through 215 )
3X-RAY DIFFRACTION3chain 'L' and (resid 1 through 110 )
4X-RAY DIFFRACTION4chain 'L' and (resid 111 through 214 )

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