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- PDB-7k8q: Crystal structure of an anti-SARS-CoV-2 human neutralizing antibo... -

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Basic information

Entry
Database: PDB / ID: 7k8q
TitleCrystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C121
Components
  • C121 Fab Heavy Chain
  • C121 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: 2 Å
AuthorsAbernathy, M.E. / 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: C121 Fab Heavy Chain
L: C121 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,6773
Polymers48,5852
Non-polymers921
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3130 Å2
ΔGint-22 kcal/mol
Surface area20340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.304, 71.304, 404.844
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

#1: Antibody C121 Fab Heavy Chain


Mass: 25965.162 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 C121 Fab Light Chain


Mass: 22619.984 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.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 3.06 Å3/Da / Density % sol: 59.77 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 5.1 / Details: 0.2 M ammonium citrate, 20% 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: 2→39.1 Å / Num. obs: 42233 / % possible obs: 99.2 % / Redundancy: 26.3 % / Biso Wilson estimate: 47.81 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.114 / Net I/σ(I): 8.4
Reflection shellResolution: 2→2.05 Å / Rmerge(I) obs: 1.36 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 2989 / CC1/2: 0.977 / Rpim(I) all: 0.81

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
Blu-Icedata collection
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 5T3Z

5t3z


Resolution: 2→36.36 Å / SU ML: 0.3004 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.6461
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2431 2059 4.88 %
Rwork0.2054 40174 -
obs0.2072 42233 98.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.47 Å2
Refinement stepCycle: LAST / Resolution: 2→36.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3247 0 6 12 3265
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083333
X-RAY DIFFRACTIONf_angle_d0.99564544
X-RAY DIFFRACTIONf_chiral_restr0.0616513
X-RAY DIFFRACTIONf_plane_restr0.0056577
X-RAY DIFFRACTIONf_dihedral_angle_d21.3759470
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.050.32141160.31572520X-RAY DIFFRACTION94.75
2.05-2.10.38581200.32872645X-RAY DIFFRACTION98.71
2.1-2.160.351280.29042583X-RAY DIFFRACTION98.76
2.16-2.220.3451400.29512614X-RAY DIFFRACTION98.78
2.22-2.290.36781400.28832628X-RAY DIFFRACTION99
2.29-2.370.34151420.28072630X-RAY DIFFRACTION98.96
2.37-2.470.271280.25132642X-RAY DIFFRACTION99.18
2.47-2.580.32581230.26522623X-RAY DIFFRACTION97.93
2.58-2.720.27781440.2572639X-RAY DIFFRACTION99.32
2.72-2.890.2891450.25432675X-RAY DIFFRACTION99.61
2.89-3.110.27451290.25332729X-RAY DIFFRACTION99.58
3.11-3.420.27251690.23152704X-RAY DIFFRACTION99.83
3.42-3.910.23291470.18932703X-RAY DIFFRACTION98.31
3.92-4.930.15331360.14052825X-RAY DIFFRACTION99.87
4.93-36.360.20671520.16343014X-RAY DIFFRACTION98.38
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)
15.264170438024.14325641153-1.755844649023.2657813597-1.471336847593.014198880710.323563617155-0.458518354238-0.04046618088850.213122903792-0.474661763214-0.728145973102-0.2239021730580.3316749479840.02852555107340.482898265904-0.01816733515740.04514150595960.418246694439-0.06436725429150.463615044844-9.882314402485.83242885242-15.2779319426
20.6913194675640.626858491089-0.06196525570085.37286339755-0.3865763504931.167688300280.134199660838-0.0956591759889-0.2683310403760.358655308984-0.257092771582-0.331645376503-0.1413555093050.05356149290190.1440736622810.4593506667310.003834233809610.0586261038940.487909077413-0.05595495450470.380483188012-13.1224258044-4.80348868595-19.0407830616
33.121024489551.164962966310.006389583647692.9005125577-0.4192605495513.14012324804-0.01272488781990.132540647670.61325139553-0.3997023606860.0722182777635-0.180166475936-0.630626928581-0.164037769429-0.03204243731250.470252662312-0.004262364037640.06464125990560.431493844119-0.04053296537760.346528140268-16.28631726770.649690192294-28.4166816769
43.64856812349-0.6718574382330.1979266490823.686079701532.382705083861.639144376140.404894833640.0608372787249-0.0234930916268-0.143412525650.0248677532539-0.245152168595-0.2067029740470.328371093055-0.4214256678750.428535773603-0.04979216184970.09885286305170.571135115093-0.04675945697420.403620577397-6.970840595161.39481622364-24.3438328901
51.758998954330.4840503983280.2101144140175.241211514221.646631966620.7757508622020.318943984455-0.117885919704-0.008839244217910.106307971398-0.124524933804-0.8471978054850.0700327037676-0.140638995561-0.1074299564860.489543448529-0.01028194101360.08092482206340.528301860011-0.08485009203420.328543647937-17.7923286398-1.58260376662-21.7196811051
60.689855660842-0.943164893616-0.2981094355491.983279655761.38358345911.17725145662-0.1441688015660.1155670125720.166389246881-0.04727638023870.204860259548-0.09274339541960.0007339651497770.0550718681543-0.06662928262340.355710938362-0.003747170280720.05168289007230.437284093336-0.02016059000540.392530189736-18.06413833619.674345176-6.98746879353
73.29107885122-0.32228197842-1.252091521341.956207715460.5180543451364.14231199051-0.2357402391770.204815627752-0.0116142452372-0.2346950751210.0159642127348-0.3310241550410.107109558218-0.105927132986-0.01261971344650.380753722516-0.0321325509812-0.008585807718950.374838125585-0.03062301037380.512702377375-16.793362765323.51995819630.664436279234
83.51638470828-1.45604823704-0.1651931163222.442287201010.09813219570244.4506003469-0.0458926093660.6125547943030.210828293459-0.5829270986910.175692622599-0.2618157725290.281562314608-0.4174837710070.05962133677110.395052382798-0.0563140177024-0.009847979544080.382295851934-0.01781961525630.388662449339-21.151399404625.1009621144-6.68565474853
95.106000884050.816244039424-1.300469806832.255975661490.7887374851016.61677769231-0.185018331629-0.290359365657-0.2483323455280.2567876642010.223342677095-0.383260585087-0.06511573852450.49013920935-0.02266206585580.3664597489750.0413928297478-0.0794372086870.250365761277-0.001936728483960.45035336891-16.89156909726.89734957747.80681923099
104.59720486844-5.50887733931-3.056955886198.772415344771.683314546284.697294170150.594260170687-1.054251477450.07095727047961.71303625921-0.173108145586-1.09936904511-0.829385204685-0.0421398745066-0.3733016798290.670466976706-0.023109996047-0.04000637640590.458884056826-0.02991630277920.55720321367-18.631368447335.18662712211.366685653
111.256370929090.1478184427391.576792904455.50072269062-0.5331821112715.30140484440.4530261706340.3751394026990.236235840836-0.00759272870225-0.5606531823370.914473384628-0.552148535451-0.7663697170850.2098963102770.4705533549790.04857038580650.01593960684730.612736971467-0.1659815272030.690896040074-40.41606734322.68227931887-22.0632550244
122.287105793470.026407842971-0.2716500697372.941117860250.3648335312641.857315958440.107192990625-0.05786175555160.1391617431940.194822735825-0.1091049831020.457880817235-0.0883985007062-0.297998681908-0.008102359310330.3808516187990.005831283479120.0812455357070.490559427707-0.126738518060.436268923412-33.4777351877-3.97856051197-21.0153159307
131.147632488731.831990656211.136493684854.379631000863.216464083272.582736290220.263100231186-0.0904783079568-0.5510658162961.25770029555-0.4940549277550.3115984810150.583934225274-0.1263877719820.606969502030.4387688296130.02121746592260.09155623222180.466570628309-0.1088349010940.620905624312-40.746207430620.4303422789-4.09398954114
147.212258954240.7190725445380.4492075969075.599858460881.14035670313.343993309020.05027056283420.4692296852940.148320620059-0.0816395399981-0.192668749133-0.671769989033-0.305033626575-0.05331405808310.1568688298040.3146445290510.0410170804221-0.004332708764180.3488674848910.004446767156220.359289714335-30.023423863734.0026734132-7.43776068684
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'H' and (resid 1 through 17 )HC1 - 171 - 17
22chain 'H' and (resid 18 through 39 )HC18 - 3918 - 39
33chain 'H' and (resid 40 through 64 )HC40 - 6440 - 65
44chain 'H' and (resid 65 through 83 )HC65 - 8366 - 87
55chain 'H' and (resid 84 through 100 )HC84 - 10088 - 104
66chain 'H' and (resid 101 through 139 )HC101 - 139116 - 149
77chain 'H' and (resid 140 through 162 )HC140 - 162150 - 172
88chain 'H' and (resid 163 through 182 )HC163 - 182173 - 192
99chain 'H' and (resid 183 through 210 )HC183 - 210193 - 220
1010chain 'H' and (resid 211 through 214 )HC211 - 214221 - 224
1111chain 'L' and (resid 1 through 23 )LD1 - 231 - 23
1212chain 'L' and (resid 24 through 104 )LD24 - 10424 - 108
1313chain 'L' and (resid 105 through 117 )LD105 - 117109 - 121
1414chain 'L' and (resid 118 through 209 )LD118 - 209122 - 213

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