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- PDB-7k8n: Crystal structure of an anti-SARS-CoV-2 human neutralizing antibo... -

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Basic information

Entry
Database: PDB / ID: 7k8n
TitleCrystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C102
Components
  • C102 Fab Heavy Chain
  • C102 Fab Light Chain
KeywordsIMMUNE SYSTEM / Human Neutralizing Antibody / SARS-CoV-2 / Receptor Binding Domain / COVID-19
Function / homologyDI(HYDROXYETHYL)ETHER
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: C102 Fab Heavy Chain
B: C102 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,55812
Polymers46,6112
Non-polymers94710
Water1,820101
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4880 Å2
ΔGint-54 kcal/mol
Surface area19590 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)88.813, 88.813, 218.858
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Space group name HallP652(x,y,z+1/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+1/3
#8: -x,-y,z+1/2
#9: y,x,-z+2/3
#10: -y,-x,-z+1/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+5/6

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Components

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Antibody , 2 types, 2 molecules AB

#1: Antibody C102 Fab Heavy Chain


Mass: 23296.098 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 C102 Fab Light Chain


Mass: 23314.793 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)

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Non-polymers , 4 types, 111 molecules

#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C4H10O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 2.65 Å3/Da / Density % sol: 53.67 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 0.2 M ammonium sulfate, 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: 0.9795 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 29, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.65→38.04 Å / Num. obs: 116041 / % possible obs: 99.9 % / Redundancy: 19.2 % / Biso Wilson estimate: 28.45 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.023 / Net I/σ(I): 15.3
Reflection shellResolution: 1.65→1.71 Å / Rmerge(I) obs: 1.48 / Num. unique obs: 6095 / CC1/2: 0.807 / Rpim(I) all: 0.334

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Blu-Icedata collection
DIALSdata reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 7BZ5
Resolution: 1.65→38.04 Å / SU ML: 0.1871 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 20.9768
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2072 3745 3.23 %
Rwork0.1965 112296 -
obs0.1968 116041 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 41.51 Å2
Refinement stepCycle: LAST / Resolution: 1.65→38.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3244 0 58 101 3403
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01513380
X-RAY DIFFRACTIONf_angle_d1.44274589
X-RAY DIFFRACTIONf_chiral_restr0.0739508
X-RAY DIFFRACTIONf_plane_restr0.0097585
X-RAY DIFFRACTIONf_dihedral_angle_d19.87391206
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.65-1.670.35691320.32424146X-RAY DIFFRACTION99.74
1.67-1.690.28821380.28154144X-RAY DIFFRACTION100
1.69-1.720.23151410.25764167X-RAY DIFFRACTION100
1.72-1.740.2721390.25234146X-RAY DIFFRACTION100
1.74-1.770.26011420.24094156X-RAY DIFFRACTION100
1.77-1.790.24891390.22554179X-RAY DIFFRACTION100
1.79-1.820.27491340.22494136X-RAY DIFFRACTION100
1.82-1.860.2321430.2154200X-RAY DIFFRACTION100
1.86-1.890.21481360.21814152X-RAY DIFFRACTION100
1.89-1.930.24541360.21284182X-RAY DIFFRACTION100
1.93-1.960.18931400.20664115X-RAY DIFFRACTION100
1.97-2.010.24691370.20044160X-RAY DIFFRACTION99.98
2.01-2.050.19451410.20864167X-RAY DIFFRACTION100
2.05-2.110.26161380.20524174X-RAY DIFFRACTION100
2.11-2.160.18911400.20784151X-RAY DIFFRACTION100
2.16-2.230.25491340.20924159X-RAY DIFFRACTION100
2.23-2.30.25861410.21874140X-RAY DIFFRACTION100
2.3-2.380.2721410.21324164X-RAY DIFFRACTION99.98
2.38-2.480.20871440.2174177X-RAY DIFFRACTION99.98
2.48-2.590.21491350.21294149X-RAY DIFFRACTION100
2.59-2.720.2441400.21624151X-RAY DIFFRACTION100
2.72-2.90.21521410.21664161X-RAY DIFFRACTION100
2.9-3.120.2541350.21354156X-RAY DIFFRACTION100
3.12-3.430.19181350.20234183X-RAY DIFFRACTION100
3.43-3.930.16721430.18264148X-RAY DIFFRACTION100
3.93-4.940.1781380.14374175X-RAY DIFFRACTION100
4.95-38.040.16981420.17764158X-RAY DIFFRACTION99.86
Refinement TLS params.

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

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
13.48882308175-0.649965113289-2.25911015723.182710479940.8502723003452.719673797960.3098512953990.5104331290980.155059622365-0.0631410801063-0.1809088315730.0683012705566-0.447378325532-0.543812277634-0.02266214858170.232523400620.1303148088950.01278100495980.3170071049220.06846002097010.16704992634737.162597876948.7904631341-18.4193543276
24.837564515620.64552861474-1.924025004253.21298380985-1.806069218321.83763204681-0.4301168051081.01263721494-0.328552737153-0.3429966713540.4578066945090.2317454265470.413351231349-0.542658281244-0.04829762115060.431904345496-0.1325530287170.07885561371330.533493877604-0.05637524329420.39888060655519.263115984524.0197074978-7.49001202217
33.053143370770.0978254766927-1.199910482162.66650484143-1.52636972643.568509162450.125797181255-0.060554459840.0974884770405-0.0637248893052-0.235093558889-0.17992954025-0.2757250777670.3505124936140.06614379090490.294969448813-0.03191554103080.03831430514440.21260773160.02164755688850.21759168956425.72779988558.7531183381-1.23383069363
42.24794611668-0.618364587379-1.145155474913.846432990690.7504602364882.58099404017-0.06284402965030.0516104925482-0.323153183203-0.05267870302760.0154636267497-0.3230097511470.3893175880950.12164631819-0.006870906288080.3111076763170.0008244331165560.03385172122390.239736847848-0.001801647368410.38795524310419.167565486723.15358055218.99456451334
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 112)
2X-RAY DIFFRACTION2chain 'A' and (resid 113 through 214)
3X-RAY DIFFRACTION3chain 'B' and (resid 1 through 108 )
4X-RAY DIFFRACTION4chain 'B' and (resid 109 through 213)

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